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.

The gap-prepulse inhibition deficit of the cortical N1-P2 complex in patients with tinnitus: The effect of gap duration.

PubMed

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

2017-05-01

The present study aimed to investigate whether gap-prepulse inhibition (GPI) deficit in patients with tinnitus occurred in the N1-P2 complex of the cortical auditory evoked potential. Auditory late responses to the intense sound of the GPI paradigm were obtained from 16 patients with tinnitus and 18 age- and hearing loss-matched controls without tinnitus. The inhibition degrees of the N1-P2 complex were assessed at 100-, 50-, and 20-ms gap durations with tinnitus-pitch-matched and non-matched frequency background noises. At the 20-ms gap condition with the tinnitus-pitch-matched frequency background noise, only the tinnitus group showed an inhibition deficit of the N1-P2 complex. The inhibition deficits were absent in both groups with longer gap durations. These findings suggested that the effect of tinnitus emerged depending on the cue onset timing and duration of the gap-prepulse. Since inhibition deficits were observed in both groups at the same 20-ms gap condition, but with the tinnitus-pitch-non-matched frequency background noise, the present study did not offer proof of concept for tinnitus filling in the gap. Additional studies on the intrinsic effects of different background frequencies on the gap processing are required in the future. Copyright © 2017 Elsevier B.V. All rights reserved.

Contrasting effect of prepulse signals on performance of Toxoplasma-infected and Toxoplasma-free subjects in an acoustic reaction times test.

PubMed

Příplatová, Lenka; Sebánková, Blanka; Flegr, Jaroslav

2014-01-01

About 30% of people on Earth have latent toxoplasmosis. Infected subjects do not express any clinical symptoms, however, they carry dormant stages of parasite Toxoplasma for the rest of their life. This form of toxoplasmosis is mostly considered harmless, however, recent studies showed its specific effects on physiology, behaviour and its associations with various diseases, including psychiatric disorders such as schizophrenia. Individuals who suffer from schizophrenia have about 2.7 times higher prevalence of Toxoplasma-seropositivity than controls, which suggests that some traits characteristic of schizophrenic patients, including the sex difference in schizophrenia onset, decrease of grey matter density in specific brain areas and modification of prepulse inhibition of startle reaction could in fact be caused by toxoplasmosis for those patients who are Toxoplasma-seropositive. We measured the effect of prepulse inhibition/facilitation of the startle reaction on reaction times. The students, 170 women and 66 men, were asked to react as quickly as possible to a startling acoustic signal by pressing a computer mouse button. Some of the startling signals were without the prepulse, some were 20 msec. preceded by a short (20 msec.) prepulse signal of lower intensity. Toxoplasma-seropositive subjects had longer reaction times than the controls. Acoustic prepulse shorted the reaction times in all subjects. This effect of prepulse on reaction times was stronger in male subjects and increased with the duration of infection, suggesting that it represented a cumulative effect of latent toxoplasmosis, rather than a fading out after effect of past acute toxoplasmosis. Different sensitivity of Toxoplasma-seropositive and Toxoplasma-seronegative subjects on effect of prepulses on reaction times (the toxoplasmosis-prepulse interaction) suggested, but of course did not prove, that the alternations of prepulse inhibition of startle reaction observed in schizophrenia patients

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

PubMed

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

2015-11-01

The gap-startle paradigm has been used as a behavioral method for tinnitus screening in animal studies. This study aimed to investigate gap prepulse inhibition (GPI) of the auditory late response (ALR) as the objective response of the gap-intense sound paradigm in humans. ALRs were recorded in response to gap-intense and no-gap-intense sound stimuli in 27 healthy subjects. The amplitudes of the baseline-to-peak (N1, P2, and N2) and the peak-to-peak (N1P2 and P2N2) were compared between two averaged ALRs. The variations in the inhibition ratios of N1P2 and P2N2 during the experiment were analyzed by increasing stimuli repetitions. The effect of stimulus parameter adjustments on GPI ratios was evaluated. No-gap-intense sound stimuli elicited greater peak amplitudes than gap-intense sound stimuli, and significant differences were found across all peaks. The overall mean inhibition ratios were significantly lower than 1.0, where the value 1.0 indicates that there were no differences between gap-intense and no-gap-intense sound responses. The initial decline in GPI ratios was shown in N1P2 and P2N2 complexes, and this reduction was nearly complete after 100 stimulus repetitions. Significant effects of gap length and interstimulus interval on GPI ratios were observed. We found significant inhibition of ALR peak amplitudes in performing the gap-intense sound paradigm in healthy subjects. The N1P2 complex represented GPI well in terms of suppression degree and test-retest reliability. Our findings offer practical information for the comparative study of healthy subjects and tinnitus patients using the gap-intense sound paradigm with the ALR. © 2015 Society for Psychophysiological Research.

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. Copyright © 2016 Elsevier Inc. All rights reserved.

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

PubMed

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

2016-01-01

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

Cannabidiol effects in the prepulse inhibition disruption induced by amphetamine.

PubMed

Pedrazzi, J F C; Issy, A C; Gomes, F V; Guimarães, F S; Del-Bel, E A

2015-08-01

The information processing appears to be deficient in schizophrenia. Prepulse inhibition (PPI), which measures the inhibition of a motor response by a weak sensory event, is considered particularly useful to understand the biology of information processing in schizophrenia patients. Drugs that facilitate dopaminergic neurotransmission such as amphetamine induce PPI disruption in human and rodents. Clinical and neurobiological findings suggest that the endocannabinoid system and cannabinoids may be implicated in the pathophysiology and treatment of schizophrenia. Cannabidiol (CBD), a non-psychotomimetic constituent of the Cannabis sativa plant, has also been reported to have potential as an antipsychotic. Our aim was to investigate if CBD pretreatment was able to prevent PPI disruption induced by amphetamine. Since one possible mechanism of CBD action is the facilitation of endocannabinoid-mediated neurotransmission through anandamide, we tested the effects of an anandamide hydrolysis inhibitor (URB597) in the amphetamine-induced PPI disruption. Male Swiss mice were treated with CBD systemic or intra-accumbens, or URB597 (systemic) prior to amphetamine and were exposed to PPI test. Amphetamine (10 mg/kg) disrupted PPI while CBD (15-60 mg/kg) or URB597 (0.1-1 mg/kg) administered alone had no effect. Pretreatment with CBD attenuated the amphetamine-disruptive effects on PPI test after systemic or intra-accumbens administration. Similar effects were also found with the inhibitor of anandamide hydrolysis. These results corroborate findings indicating that CBD induces antipsychotic-like effects. In addition, they pointed to the nucleus accumbens as a possible site of these effects. The increase of anandamide availability may be enrolled in the CBD effects.

Corticosteroid dependent and independent effects of a cannabinoid agonist on core temperature, motor activity, and prepulse inhibition of the acoustic startle reflex in Wistar rats.

PubMed

Avdesh, Avdesh; Cornelisse, Vincent; Martin-Iverson, Mathew Thomas

2012-03-01

There are inconsistent reports on the effects of cannabinoid agonists on prepulse inhibition of the startle reflex (PPI) with increases, decreases, and no effects. It has been hypothesized that the conflicting observations may be as a result of modulation of the effects of cannabinoid agonists by the regulation of corticosteroid release. The purpose of the present study was to determine the effects of CP55940, a cannabinoid agonist, and metyrapone, a corticosteroid synthesis inhibitor on core temperature, motor activity, the startle reflex, and PPI. Startle responses were measured in 64 male Wistar rats while varying startling stimulus intensities, analogous to dose-response curves. A stimulus potency measure (ES(50)) and a response measure, the maximal achievable response (R (MAX)) were derived from the stimulus-response curves. CP55940 reduced core temperature and motor activity; these effects were potentiated by metyrapone. CP55940 increased R (MAX) of startle in the absence of a prepulse by a corticosteroid-dependent mechanism but decreased it when metyrapone was administered before CP55940, a corticosteroid-independent mechanism. The inverse of stimulus potency (ES(50)) was not affected by either drug alone but was increased by the combined drugs. CP55940 increased the prepulse motor gating effects and decreased the prepulse sensory gating effects of the same prepulses but only when given after metyrapone. The most parsimonious interpretation of these effects is that CP55940 has some effects through corticosteroid-dependent actions and opposite effects by corticosteroid-independent actions. These two putative sites of actions affect stimulus gating opposite to their effects on response gating.

Routine post-weaning handling of rats prevents isolation rearing-induced deficit in prepulse inhibition.

PubMed

Rosa, M L N M; Silva, R C B; Moura-de-Carvalho, F T; Brandão, M L; Guimarães, F S; Del Bel, E A

2005-11-01

Rats reared under isolation conditions from weaning present a number of behavioral changes compared to animals reared under social conditions (group housing). These changes include deficits in prepulse inhibition (PPI) of the startle reflex to a loud sound. PPI refers to the reduction of the magnitude of the startle reflex when a relatively weak stimulus (the prepulse) precedes by an appropriate time interval the intense startle-elicing stimulus (the pulse). PPI is useful for studying sensorimotor integration. The present study evaluated the effect of handling on the impairment of PPI induced by isolation-rearing. Male Wistar rats (N = 11-15/group) were housed in groups (5 per cage and handled three times a week) or isolated (housed individually) since weaning (21 days) for 10 weeks when they reach approximately 150 g. The isolated rats were divided into "minimally handled" animals (handled once a week for cleaning purposes only) or "handled" animals (handled three times a week). This handling consisted of grasping the rat by the tail and moving it to a clean cage (approximately 5 s). A statistically significant reduction (52%) in the PPI test was found only in the isolated group with minimal handling while no difference was seen between grouped animals and isolated handled animals. These results indicate that isolation rearing causes disruption in the PPI at adult age, which serves as an index of attention deficit. This change in the sensory processing of information induced by post-weaning isolation can be prevented by handling during the development of the animal.

Association between arginine vasopressin 1a receptor (AVPR1a) promoter region polymorphisms and prepulse inhibition.

PubMed

Levin, Raz; Heresco-Levy, Uriel; Bachner-Melman, Rachel; Israel, Salomon; Shalev, Idan; Ebstein, Richard P

2009-07-01

Arginine vasopressin and the arginine vasopressin 1a (AVPR1a) gene contribute to a range of social behaviors both in lower vertebrates and in humans. Human promoter-region microsatellite repeat regions (RS1 and RS3) in the AVPR1a gene region have been associated with autism spectrum disorders, prosocial behavior and social cognition. Prepulse inhibition (PPI) of the startle response to auditory stimuli is a largely autonomic response that resonates with social cognition in both animal models and humans. Reduced PPI has been observed in disorders including schizophrenia that are distinguished by deficits in social skills. In the current investigation association was examined between PPI and the AVPR1a RS1 and RS repeat regions and PPI in a group of 113 nonclinical subjects. Using a robust family-based strategy, association was observed between AVPR1a promoter-region repeat length, especially RS3) and PPI (30 ms: global p=0.04; 60 ms p=0.006; 120 ms p=0.008). Notably, longer RS3 alleles were associated with greater levels of prepulse inhibition. Using a short/long classification scheme for the repeat regions, significant association was also observed between all three PPI intervals (30, 60 and 120 ms) and both RS1 and RS3 polymorphisms (PBAT: FBAT-PC(2) statistic p=0.047). Tests of within-subject effects (SPSS GLM) showed significant sexxRS3 interactions at 30 ms (p=0.045) and 60 ms (p=0.01). Longer alleles, especially in male subjects, are associated with significantly higher PPI response, consistent with a role for the promoter repeat region in partially molding social behavior in both animals and humans. This is the first report in humans demonstrating a role of the AVPR1a gene in contributing to the PPI response to auditory stimuli.

Disturbed prepulse inhibition in patients with schizophrenia is consequential to dysfunction of selective attention.

PubMed

Scholes, Kirsty E; Martin-Iverson, Mathew T

2010-03-01

Controversy exists as to the cause of disturbed prepulse inhibition (PPI) in patients with schizophrenia. This study aimed to clarify the nature of PPI in schizophrenia using improved methodology. Startle and PPI were measured in 44 patients with schizophrenia and 32 controls across a range of startling stimulus intensities under two conditions, one while participants were attending to the auditory stimuli (ATTEND condition) and one while participants completed a visual task in order to ensure they were ignoring the auditory stimuli (IGNORE condition). Patients showed reduced PPI of R(MAX) (reflex capacity) and increased PPI of Hillslope (reflex efficacy) only under the INGORE condition, and failed to show the same pattern of attentional modulation of the reflex parameters as controls. In conclusion, disturbed PPI in schizophrenia appears to result from deficits in selective attention, rather than from preattentive dysfunction.

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. Copyright © 2015 Elsevier Inc. All rights reserved.

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

PubMed

Longenecker, R J; Galazyuk, A V

2012-11-16

Recently prepulse inhibition of the acoustic startle reflex (ASR) became a popular technique for tinnitus assessment in laboratory animals. This method confers a significant advantage over the previously used time-consuming behavioral approaches utilizing basic mechanisms of conditioning. Although this technique has been successfully used to assess tinnitus in different laboratory animals, many of the finer details of this methodology have not been described enough to be replicated, but are critical for tinnitus assessment. Here we provide detail description of key procedures and methodological issues that provide guidance for newcomers with the process of learning to correctly apply gap detection techniques for tinnitus assessment in laboratory animals. The major categories of these issues include: refinement of hardware for best performance, optimization of stimulus parameters, behavioral considerations, and identification of optimal strategies for data analysis. This article is part of a Special Issue entitled: Tinnitus Neuroscience. Copyright © 2012. Published by Elsevier B.V.

Differential effects of antipsychotic and propsychotic drugs on prepulse inhibition and locomotor activity in Roman high- (RHA) and low-avoidance (RLA) rats

PubMed Central

Oliveras, Ignasi; Sánchez-González, Ana; Sampedro-Viana, Daniel; Piludu, Maria Antonietta; Río-Alamos, Cristóbal; Giorgi, Osvaldo; Corda, Maria G.; Aznar, Susana; González-Maeso, Javier; Gerbolés, Cristina; Blázquez, Gloria; Cañete, Toni; Tobeña, Adolf

2017-01-01

Rationale Animal models with predictive and construct validity are necessary for developing novel and efficient therapeutics for psychiatric disorders. Objectives We have carried out a pharmacological characterization of the Roman high-(RHA-I) and low-avoidance (RLA-I) rat strains with different acutely administered propsychotic (DOI, MK-801) and antipsychotic drugs (haloperidol, clozapine), as well as apomorphine, on prepulse inhibition (PPI) of startle and locomotor activity (activity cages). Results RHA-I rats display a consistent deficit of PPI compared with RLA-I rats. The typical antipsychotic haloperidol (dopamine D2 receptor antagonist) reversed the PPI deficit characteristic of RHA-I rats (in particular at 65 and 70 dB prepulse intensities) and reduced locomotion in both strains. The atypical antipsychotic clozapine (serotonin/dopamine receptor antagonist) did not affect PPI in either strain, but decreased locomotion in a dose-dependent manner in both rat strains. The mixed dopamine D1/D2 agonist, apomorphine, at the dose of 0.05 mg/kg, decreased PPI in RHA-I, but not RLA-I rats. The hallucinogen drug DOI (5-HT2A agonist; 0.1–1.0 mg/kg) disrupted PPI in RLA-I rats in a dose-dependent manner at the 70 dB prepulse intensity, while in RHA-Irats, only the 0.5 mg/kg dose impaired PPI at the 80 dB prepulse intensity. DOI slightly decreased locomotion in both strains. Finally, clozapine attenuated the PPI impairment induced by the NMDA receptor antagonist MK-801 only in RLA-I rats. Conclusions These results add experimental evidence to the view that RHA-I rats represent a model with predictive and construct validity of some dopamine and 5-HT2A receptor-related features of schizophrenia. PMID:28154892

Gap prepulse inhibition and auditory brainstem-evoked potentials as objective measures for tinnitus in guinea pigs

PubMed Central

Dehmel, Susanne; Eisinger, Daniel; Shore, Susan E.

2012-01-01

Tinnitus or ringing of the ears is a subjective phantom sensation necessitating behavioral models that objectively demonstrate the existence and quality of the tinnitus sensation. The gap detection test uses the acoustic startle response elicited by loud noise pulses and its gating or suppression by preceding sub-startling prepulses. Gaps in noise bands serve as prepulses, assuming that ongoing tinnitus masks the gap and results in impaired gap detection. This test has shown its reliability in rats, mice, and gerbils. No data exists for the guinea pig so far, although gap detection is similar across mammals and the acoustic startle response is a well-established tool in guinea pig studies of psychiatric disorders and in pharmacological studies. Here we investigated the startle behavior and prepulse inhibition (PPI) of the guinea pig and showed that guinea pigs have a reliable startle response that can be suppressed by 15 ms gaps embedded in narrow noise bands preceding the startle noise pulse. After recovery of auditory brainstem response (ABR) thresholds from a unilateral noise over-exposure centered at 7 kHz, guinea pigs showed diminished gap-induced reduction of the startle response in frequency bands between 8 and 18 kHz. This suggests the development of tinnitus in frequency regions that showed a temporary threshold shift (TTS) after noise over-exposure. Changes in discharge rate and synchrony, two neuronal correlates of tinnitus, should be reflected in altered ABR waveforms, which would be useful to objectively detect tinnitus and its localization to auditory brainstem structures. Therefore, we analyzed latencies and amplitudes of the first five ABR waves at suprathreshold sound intensities and correlated ABR abnormalities with the results of the behavioral tinnitus testing. Early ABR wave amplitudes up to N3 were increased for animals with tinnitus possibly stemming from hyperactivity and hypersynchrony underlying the tinnitus percept. Animals that did not

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

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

PubMed

Liuzzo, Andrea; Gray, Lincoln; Wallace, Matthew; Gabriele, Mark

2014-08-01

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 5-300ms 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 (EphA4(lacZ/+), EphA4(lacZ/lacZ)), and knockout ephrin-B3 mice (ephrin-B3 (+/-, -/-)). Control and EphA4(lacZ/+s)trains showed robust PPI (up to 75% decrement in ASR) to an offset of a 70dB SPL background noise at 50ms 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 changes

Dissociable effects of the d- and l- enantiomers of govadine on the disruption of prepulse inhibition by MK-801 and apomorphine in male Long-Evans rats.

PubMed

Lins, Brittney R; Marks, Wendie N; Phillips, Anthony G; Howland, John G

2017-04-01

The search for novel antipsychotic drugs to treat schizophrenia is driven by the poor treatment efficacy, serious side effects, and poor patient compliance of current medications. Recently, a class of compounds known as tetrahydroprotoberberines, which includes the compound d,l -govadine, have shown promise in preclinical rodent tests relevant to schizophrenia. To date, the effect of govadine on prepulse inhibition (PPI), a test for sensorimotor gating commonly used to assess the effects of putative treatments for schizophrenia, has not been determined. The objective of the present study was to determine the effects of each enantiomer of govadine ( d - and l -govadine) on PPI alone and its disruption by the distinct pharmacological compounds apomorphine and MK-801. Male Long-Evans rats were treated systemically with d - or l -govadine and apomorphine or MK-801 prior to PPI. The PPI paradigm employed here included parametric manipulations of the prepulse intensity and the interval between the prepulse and pulse. Acute MK-801 (0.15 mg/kg) significantly increased the startle response to startle pulses alone, while both MK-801 and apomorphine (0.2 mg/kg) significantly increased reactivity to prepulse-alone trials. Both MK-801 and apomorphine disrupted PPI. In addition, d -govadine alone significantly disrupted PPI in the apomorphine experiment. Pretreatment with l -, but not d -, govadine (1.0 mg/kg) blocked the effect of apomorphine and MK-801 on PPI. Treatment of rats with l -govadine alone (0.3, 1.0, 3.0 mg/kg) also dose-dependently increased PPI. Given the high affinity of l -govadine for dopamine D2 receptors, these results suggest that further testing of l -govadine as an antipsychotic is warranted.

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. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of Olanzapine, Risperidone and Haloperidol on Prepulse Inhibition in Schizophrenia Patients: A Double-Blind, Randomized Controlled Trial

PubMed Central

Wynn, Jonathan K.; Green, Michael F.; Sprock, Joyce; Light, Gregory A.; Widmark, Clifford; Reist, Christopher; Erhart, Stephen; Marder, Stephen R.; Mintz, Jim; Braff, David L.

2009-01-01

Prepulse inhibition (PPI), whereby the startle eyeblink response is inhibited by a relatively weak non-startling stimulus preceding the powerful startle eliciting stimulus, is a measure of sensorimotor gating and has been shown to be deficient in schizophrenia patients. There is considerable interest in whether conventional and/or atypical antipsychotic medications can “normalize” PPI deficits in schizophrenia patients. 51 schizophrenia patients participated in a randomized, double-blind controlled trial on the effects of three commonly-prescribed antipsychotic medications (risperidone, olanzapine, or haloperidol) on PPI, startle habituation, and startle reactivity. Patients were tested at baseline, Week 4 and Week 8. Mixed model regression analyses revealed that olanzapine significantly improved PPI from Week 4 to Week 8, and that at Week 8 patients receiving olanzapine produced significantly greater PPI than those receiving risperidone, but not haloperidol. There were no effects of medication on startle habituation or startle reactivity. These results support the conclusion that olanzapine effectively increased PPI in schizophrenia patients, but that risperidone and haloperidol had no such effects. The results are discussed in terms of animal models, neural substrates, and treatment implications. PMID:17662577

Deletion of striatal adenosine A2A receptor spares latent inhibition and prepulse inhibition but impairs active avoidance learning

PubMed Central

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

2013-01-01

Following early clinical leads, the adenosine A2AR receptor (A2AR) 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 A2AR’s unique modulatory action over glutamatergic in addition to dopaminergic signaling. Through the antagonistic interaction with the dopamine D2 receptor, and by regulating glutamate release and N-methyl-d-aspartate receptor function, striatal A2AR is ideally positioned to fine-tune the dopamine-glutamate balance whose disturbance is implicated in the pathophysiology of schizophrenia. However, the precise function of striatal A2ARsin the regulation of schizophrenia-relevant behavior is poorly understood. Here, we tested the impact of conditional striatum-specific A2AR knockout (st-A2AR-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-A2AR-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 – 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 A2ARs– a finding that may undermine the hypothesized importance of A2AR in the genesis and/or treatment of schizophrenia. PMID:23276608

A large single ethnicity study of prepulse inhibition in schizophrenia: Separate analysis by sex focusing on effect of symptoms.

PubMed

Matsuo, Junko; Ota, Miho; Hori, Hiroaki; Hidese, Shinsuke; Teraishi, Toshiya; Ishida, Ikki; Hiraishi, Moeko; Kunugi, Hiroshi

2016-11-01

Deficits in sensorimotor gating, as measured with prepulse inhibition (PPI), have been considered an endophenotype of schizophrenia. However, the question remains whether these deficits are related to current symptoms. This single site study aimed to explore clinical features related to the modulation of startle reflex in a large sample of Japanese patients with schizophrenia (DSM-IV). The subjects comprised 181 patients and 250 healthy controls matched for age and sex. Schizophrenia symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Startle reflex to acoustic stimuli was recorded using a startle stimulus of 115 dB and a prepulse of four different conditions (intensity: 86 dB or 90 dB; lead interval: 60 ms or 120 ms). Patients exhibited significantly reduced startle magnitude (p < 0.001), habituation (p = 0.001), and PPI (90 dB, 60 ms, p = 0.016; 90 dB, 120 ms, p = 0.001) compared with controls. Patients of both sexes exhibited significantly lower habituation and PPI (90 dB, 120 ms) compared with the same sex controls. We could not detect a significant correlation with any clinical variable in the entire patients, however, when men and women were examined separately, there was a negative correlation with the PANSS cognitive domain (ρ = -0.33, p = 0.008) in men, but not in women. Moreover, when patients were subdivided into four clusters, two clusters with high positive symptoms showed significant PPI deficits in men. Our results suggest that sensorimotor gating is impaired in schizophrenia of both sexes, and PPI deficits may be related to thought disturbance and disorganization in male patients with schizophrenia. Copyright © 2016 Elsevier Ltd. All rights reserved.

Naringin ameliorates diabetic nephropathy by inhibiting NADPH oxidase 4.

PubMed

Zhang, Junwei; Yang, Suxia; Li, Huicong; Chen, Fang; Shi, Jun

2017-06-05

Naringin, a naturally flavanone glycoside, has been previously demonstrated to alleviate diabetic kidney disease by inhibiting oxidative stress and inflammatory reaction. However, the underlying mechanism of naringin in diabetic nephropathy (DN) has not been fully elucidated. Here, the beneficial effect of naringin on DN in streptozotocin (STZ)-induced DN rats and high glucose (HG)-induced podocytes and its underlying mechanism were elaborated. The result revealed that naringin alleviated STZ-induced renal dysfunction and injury in DN rats, relieved STZ-induced oxidative stress in vivo and inhibited HG-induced apoptosis and reactive oxygen species level i20n vitro. More importantly, naringin inhibited NOX4 expression at mRNA and protein levels in STZ-induced DN rats and HG-induced podocytes. Loss of function indicated that NADPH oxidases 4 (NOX4) down-regulation suppressed apoptosis and reactive oxygen species level in HG-treated podocytes. Take together, this study demonstrated that naringin ameliorates diabetic nephropathy by inhibiting NOX4, contributing to a better understanding of the progression of DN. Copyright © 2017 Elsevier B.V. All rights reserved.

The maternal immune activation (MIA) model of schizophrenia produces pre-pulse inhibition (PPI) deficits in both juvenile and adult rats but these effects are not associated with maternal weight loss.

PubMed

Wolff, Amy R; Bilkey, David K

2010-12-01

The developmental onset of deficits in sensorimotor-gating was examined in the maternal immune activation (MIA) animal model of schizophrenia. Pre-pulse inhibition (PPI) deficits were evident in juvenile MIA rats. This parallels the sensorimotor-gating deficits observed in groups at high-risk of schizophrenia. PPI deficits were independent of maternal weight loss following the MIA manipulation, suggesting that this measure may not be a useful marker of treatment efficacy. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Iron Deficiency with or without Anemia Impairs Prepulse Inhibition of the Startle Reflex

PubMed Central

Pisansky, Marc T.; Wickham, Robert J.; Su, Jianjun; Fretham, Stephanie; Yuan, Li-Lian; Sun, Mu; Gewirtz, Jonathan C.; Georgieff, Michael K.

2013-01-01

Iron deficiency (ID) during early life causes long-lasting detrimental cognitive sequelae, many of which are linked to alterations in hippocampus function, dopamine synthesis, and the modulation of dopaminergic circuitry by the hippocampus. These same features have been implicated in the origins of schizophrenia, a neuropsychiatric disorder with significant cognitive impairments. Deficits in sensorimotor gating represent a reliable endophenotype of schizophrenia that can be measured by prepulse inhibition (PPI) of the acoustic startle reflex. Using two rodent model systems, we investigated the influence of early-life ID on PPI in adulthood. To isolate the role of hippocampal iron in PPI, our mouse model utilized a timed (embryonic day 18.5), hippocampus-specific knockout of Slc11a2, a gene coding an important regulator of cellular iron uptake, the divalent metal transport type 1 protein (DMT-1). Our second model used a classic rat dietary-based global ID during gestation, a condition that closely mimics human gestational ID anemia (IDA). Both models exhibited impaired PPI in adulthood. Furthermore, our DMT-1 knockout model displayed reduced long-term potentiation (LTP) and elevated paired pulse facilitation (PPF), electrophysiological results consistent with previous findings in the IDA rat model. These results, in combination with previous findings demonstrating impaired hippocampus functioning and altered dopaminergic and glutamatergic neurotransmission, suggest that iron availability within the hippocampus is critical for the neurodevelopmental processes underlying sensorimotor gating. Ultimately, evidence of reduced PPI in both of our models may offer insights into the roles of fetal ID and the hippocampus in the pathophysiology of schizophrenia. PMID:23733517

Association between violent behaviour and impaired prepulse inhibition of the startle response in antisocial personality disorder and schizophrenia.

PubMed

Kumari, Veena; Das, Mrigen; Hodgins, Sheilagh; Zachariah, Elizabeth; Barkataki, Ian; Howlett, Michael; Sharma, Tonmoy

2005-03-07

Violent behaviour has a strong association with antisocial personality disorder (APD) and schizophrenia. Although developments in the understanding of socio-environmental factors associated with violence should not be ignored, advances in prevention and treatment of violent behaviour would benefit by improved understanding of its neurobiological and cognitive basis. The authors, therefore, investigated prepulse inhibition (PPI) of the startle response in APD and schizophrenia in relation to a history of serious violence. The neural substrates of PPI, especially the hippocampus, amygdala, thalamus and basal ganglia, are implicated in violence as well as in APD and schizophrenia. The study included four groups: (i) patients with APD and a history of violence, (ii) patients with schizophrenia and a history of violence, (iii) patients with schizophrenia without a history of violence, and (iv) healthy subjects with no history of violence or a mental disorder. All subjects were assessed identically on acoustic PPI. Compared to healthy subjects, significantly reduced PPI occurred in APD, violent schizophrenia and non-violent schizophrenia patients. Although PPI did not significantly differentiate the three clinical groups, high ratings of violence were modestly associated with reduced PPI across the entire study sample. Violent patients with impulsive and premeditated violence showed comparable PPI. The association between violent behaviour and impaired PPI suggests that neural structures and functions underlying PPI are implicated in (inhibition of) violence.

Epigallocatechin-3-gallate ameliorates intrahepatic cholestasis of pregnancy by inhibiting matrix metalloproteinase-2 and matrix metalloproteinase-9.

PubMed

Zhang, Mei; Xu, Meimei

2017-10-01

Matrix metalloproteinase (MMP)-2 and matrix metalloproteinase-9 are involved in many illnesses affecting pregnant women, including intrahepatic cholestasis of pregnancy (ICP), a serious liver abnormality during pregnancy. Epigallocatechin-3-gallate (EGCG) has been widely reported to inhibit activities of MMP-2 and MMP-9. We aimed to investigate the role of EGCG in ameliorating ICP symptoms in a rat model. Using 17α-ethinylestradiol to induce ICP in pregnant rats, we investigated the efficacy of EGCG administration on ICP symptoms, including bile flow rate, total bile acids (TBA) and MMP-2 and MMP-9 activities. Correlation study was conducted among levels of the two MMPs with other ICP symptoms. In ICP rats, activities of both MMP-2 and MMP-9 were significantly elevated. EGCG administration could inhibit the upregulation of MMP-2 and MMP-9 post-transcriptionally. Furthermore, EGCG ameliorated ICP symptoms, as evidenced by restored bile flow rate and TBA, showing efficient treatment outcomes. At last, levels of TBA and the two MMPs were found to be strongly correlated. Our study demonstrates that, for the first time, the efficacy of EGCG in ameliorating ICP symptoms by inhibiting both MMP-2 and MMP-9, which supports its potential as a novel drug in ameliorating ICP. © 2017 Société Française de Pharmacologie et de Thérapeutique.

Rivastigmine improves isolation rearing-induced prepulse inhibition deficits via muscarinic acetylcholine receptors in mice.

PubMed

Higashino, Kosuke; Ago, Yukio; Umeki, Takahiro; Hasebe, Shigeru; Onaka, Yusuke; Hashimoto, Hitoshi; Takuma, Kazuhiro; Matsuda, Toshio

2016-02-01

The acetylcholinesterase inhibitors donepezil, galantamine, and rivastigmine are used for the treatment of Alzheimer's disease. We previously demonstrated that donepezil and galantamine differentially affect isolation rearing-induced prepulse inhibition (PPI) deficits and that this might be due to differential effects on brain muscarinic acetylcholine (mACh) receptor function in mice. We examined the effects of rivastigmine on isolation rearing-induced PPI deficits, brain ACh levels, and mACh receptor function in mice. Acoustic startle responses were measured in a startle chamber. Microdialysis was performed, and the levels of dopamine and ACh in the prefrontal cortex were measured. Rivastigmine (0.3 mg/kg) improved PPI deficits, and this improvement was antagonized by the mACh receptor antagonist telenzepine but not by the nicotinic ACh receptor antagonist mecamylamine. Rivastigmine increased extracellular ACh levels by approximately 2-3-fold, less than the increase produced by galantamine. Rivastigmine enhanced the effect of the mACh receptor agonist N-desmethylclozapine on prefrontal dopamine release, a marker of mACh receptor function, and this increase was blocked by telenzepine. In contrast, galantamine did not affect N-desmethylclozapine-induced dopamine release. Furthermore, rivastigmine did not affect cortical dopamine release induced by the serotonin1A receptor agonist osemozotan, suggesting that the effect of rivastigmine has specificity for mACh receptors. Taken together with our previous finding that marked increases in ACh levels are required for the PPI deficit improvement induced by galantamine, our present results suggest that rivastigmine improves isolation rearing-induced PPI deficits by increasing ACh levels and by concomitantly enhancing mACh receptor function.

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

PubMed

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

2016-04-01

The postpartum period is characterized by a post-withdrawal hormonal status, sleep deprivation, and susceptibility to affective disorders. Postpartum mothering involves automatic and attentional processes to screen out new external as well as internal stimuli. The present study investigated sensorimotor gating in relation to sleep duration, depression, as well as catecholaminergic and oxytocinergic genotypes in postpartum women. Prepulse inhibition (PPI) of the startle reflex and startle reactivity were assessed two months postpartum in 141 healthy and 29 depressed women. The catechol-O-methyltransferase (COMT) Val158Met, and oxytocin receptor (OXTR) rs237885 and rs53576 polymorphisms were genotyped, and data on sleep duration were collected. Short sleep duration (less than four hours in the preceding night) and postpartum depression were independently associated with lower PPI. Also, women with postpartum depression had higher startle reactivity in comparison with controls. The OXTR rs237885 genotype was related to PPI in an allele dose-dependent mode, with T/T healthy postpartum women carriers displaying the lowest PPI. Reduced sensorimotor gating was associated with sleep deprivation and depressive symptoms during the postpartum period. Individual neurophysiological vulnerability might be mediated by oxytocinergic genotype which relates to bonding and stress response. These findings implicate the putative relevance of lower PPI of the startle response as an objective physiological correlate of liability to postpartum depression. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

Deficient prepulse inhibition in schizophrenia in a multi-site cohort: Internal replication and extension.

PubMed

Swerdlow, Neal R; Light, Gregory A; Thomas, Michael L; Sprock, Joyce; Calkins, Monica E; Green, Michael F; Greenwood, Tiffany A; Gur, Raquel E; Gur, Ruben C; Lazzeroni, Laura C; Nuechterlein, Keith H; Radant, Allen D; Seidman, Larry J; Siever, Larry J; Silverman, Jeremy M; Stone, William S; Sugar, Catherine A; Tsuang, Debby W; Tsuang, Ming T; Turetsky, Bruce I; Braff, David L

2017-05-23

The Consortium on the Genetics of Schizophrenia (COGS) collected case-control endophenotype and genetic information from 2457 patients and healthy subjects (HS) across 5 test sites over 3.5 years. Analysis of the first "wave" (W1) of 1400 subjects identified prepulse inhibition (PPI) deficits in patients vs. HS. Data from the second COGS "wave" (W2), and the combined W(1+2), were used to assess: 1) the replicability of PPI deficits in this design; 2) the impact of response criteria on PPI deficits; and 3) PPI in a large cohort of antipsychotic-free patients. PPI in W2 HS (n=315) and schizophrenia patients (n=326) was compared to findings from W1; planned analyses assessed the impact of diagnosis, "wave" (1 vs. 2), and startle magnitude criteria. Combining waves allowed us to assess PPI in 120 antipsychotic-free patients, including many in the early course of illness. ANOVA of all W(1+2) subjects revealed robust PPI deficits in patients across "waves" (p<0.0004). Strict response criteria excluded almost 39% of all subjects, disproportionately impacting specific subgroups; ANOVA in this smaller cohort confirmed no significant effect of "wave" or "wave x diagnosis" interaction, and a significant effect of diagnosis (p<0.002). Antipsychotic-free, early-illness patients had particularly robust PPI deficits. Schizophrenia-linked PPI deficits were replicable across two multi-site "waves" of subjects collected over 3.5years. Strict response criteria disproportionately excluded older, male, non-Caucasian patients with low-normal hearing acuity. These findings set the stage for genetic analyses of PPI using the combined COGS wave 1 and 2 cohorts. Copyright © 2017 Elsevier B.V. All rights reserved.

The effects of prepulse-blink reflex trial repetition and prepulse change on blink reflex modification at short and long lead intervals.

PubMed

Lipp, O V; Siddle, D A

1998-01-01

Prepulse inhibition and facilitation of the blink reflex are said to reflect different responses elicited by the lead stimulus, transient detection and orienting response respectively. Two experiments investigated the effects of trial repetition and lead stimulus change on blink modification. It was hypothesized that these manipulations will affect orienting and thus blink facilitation to a greater extent than they will affect transient detection and thus blink inhibition. In Experiment 1 (N = 64), subjects were trained with a sequence of 12 lead stimulus and 12 blink stimulus alone presentations, and 24 lead stimulus-blink stimulus pairings. Lead interval was 120 ms for 12 of the trials and 2000 ms for the other 12. For half the subjects this sequence was followed by a change in pitch of the lead stimulus. In Experiment 2 (N = 64), subjects were trained with a sequence of 36 blink alone stimuli and 36 lead stimulus-blink stimulus pairings. The lead interval was 120 ms for half the subjects and 2000 ms for the other half. The pitch of the lead stimulus on prestimulus trials 31-33 was changed for half the subjects in each group. In both experiments, the amount of blink inhibition decreased during training whereas the amount of blink facilitation remained unchanged. Lead stimulus change had no effect on blink modification in either experiment although it resulted in enhanced skin conductance responses and greater heart rate deceleration in Experiment 2. The present results are not consistent with the notion that blink facilitation is linked to orienting whereas blink inhibition reflects a transient detection mechanism.

Systemic inhibition of Janus kinase induces browning of white adipose tissue and ameliorates obesity-related metabolic disorders.

PubMed

Qurania, Kikid Rucira; Ikeda, Koji; Wardhana, Donytra Arby; Barinda, Agian Jeffilano; Nugroho, Dhite Bayu; Kuribayashi, Yuko; Rahardini, Elda Putri; Rinastiti, Pranindya; Ryanto, Gusty Rizky Teguh; Yagi, Keiko; Hirata, Ken-Ichi; Emoto, Noriaki

2018-07-07

Browning of white adipose tissue is a promising strategy to tackle obesity. Recently, Janus kinase (JAK) inhibition was shown to induce white-to-brown metabolic conversion of adipocytes in vitro; however effects of JAK inhibition on browning and systemic metabolic health in vivo remain to be elucidated. Here, we report that systemic administration of JAK inhibitor (JAKi) ameliorated obesity-related metabolic disorders. Administration of JAKi in mice fed a high-fat diet increased UCP-1 and PRDM16 expression in white adipose tissue, indicating the browning of white adipocyte. Food intake was increased in JAKi-treated mice, while the body weight and adiposity was similar between the JAKi- and vehicle-treated mice. In consistent with the browning, thermogenic capacity was enhanced in mice treated with JAKi. Chronic inflammation in white adipose tissue was not ameliorated by JAKi-treatment. Nevertheless, insulin sensitivity was well preserved in JAKi-treated mice comparing with that in vehicle-treated mice. Serum levels of triglyceride and free fatty acid were significantly reduced by JAKi-treatment, which is accompanied by ameliorated hepatosteatosis. Our data demonstrate that systemic administration of JAKi has beneficial effects in preserving metabolic health, and thus inhibition of JAK signaling has therapeutic potential for the treatment of obesity and its-related metabolic disorders. Copyright © 2018 Elsevier Inc. All rights reserved.

Involvement of decreased muscarinic receptor function in prepulse inhibition deficits in mice reared in social isolation

PubMed Central

Koda, K; Ago, Y; Yano, K; Nishimura, M; Kobayashi, H; Fukada, A; Takuma, K; Matsuda, T

2011-01-01

BACKGROUND AND PURPOSE We have previously reported that galantamine, a weak acetylcholinesterase inhibitor, improves prepulse inhibition (PPI) deficits in mice reared in social isolation. ACh receptors are involved in the underlying mechanism of PPI, but whether rearing in social isolation causes dysfunction of the cholinergic system is unknown. In this study, we examined the involvement of muscarinic receptors in the improvement of PPI deficits induced by galantamine, and whether the cholinergic system is altered in mice reared in isolation. EXPERIMENTAL APPROACH Three-week-old male ddY mice were housed in isolated cages for 6 weeks before the initiation of experiments to create PPI deficits. Cholinergic functions were determined by measuring the behavioural and neurochemical responses to nicotinic and muscarinic receptor agonists. KEY RESULTS The improvement by galantamine of social isolation-induced PPI deficits was blocked by scopolamine, a non-selective muscarinic antagonist, and telenzepine, a preferential M1 receptor antagonist. Activation of M1 receptors improved social isolation-induced PPI deficits. Social isolation did not affect choline acetyltransferase and acetylcholinesterase activities in the prefrontal cortex and hippocampus, but it reduced the locomotor-suppressive response to muscarinic agonist oxotremorine, but not to nicotine. The isolation also attenuated the M1 receptor agonist N-desmethylclozapine-induced increase in prefrontal dopamine release. CONCLUSIONS AND IMPLICATIONS Galantamine improves PPI deficits of mice reared in social isolation via activation of M1 receptors. Social isolation reduces the muscarinic, especially M1, receptor function and this is involved in PPI deficits. PMID:20958289

Osthole ameliorates renal ischemia-reperfusion injury by inhibiting inflammatory response.

PubMed

Zheng, Yi; Lu, Min; Ma, Lulin; Zhang, Shudong; Qiu, Min; Ma, Xin

2013-01-01

Renal ischemia-reperfusion (I/R) injury is a primary cause of acute renal failure that results in high mortality. This study aimed to investigate the effect of osthole, a natural coumarin derivative, on renal I/R injury in a rat model. Rats were randomly allocated to the sham operation + vehicle, I/R + vehicle, and I/R + osthole groups. Renal I/R injury was induced by clamping the left renal artery for 45 min followed by 12 h of reperfusion and a contralateral nephrectomy. Osthole (40 mg/kg) was intraperitoneally injected 30 min before inducing I/R. Renal function and histological damage were determined subsequently. Myeloperoxidase activity, monocyte/macrophage infiltration, as well as tumor necrosis factor-α, IL-1β, and activated p38 mitogen-activated protein kinase expression in kidneys were also assessed. Osthole treatment significantly ameliorated I/R-induced renal functional and morphological injuries. Moreover, osthole treatment attenuated myeloperoxidase activity, monocyte/macrophage infiltration, and tumor necrosis factor-α, IL-1β, and activated p38 mitogen-activated protein kinase expression in kidneys. Osthole treatment ameliorates renal I/R injury by inhibiting inflammatory responses in kidneys. Thus, osthole may represent a novel practical strategy to prevent renal I/R injury. Copyright © 2013 S. Karger AG, Basel.

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

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

Li, M., E-mail: limo@nint.ac.cn; Li, Y.; State Key Laboratory of Intense Pulsed Radiation Simulation and Effect, Northwest Institute of Nuclear Technology, Xi'an 710024

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 themore » 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.« less

Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases.

PubMed

Park, Sung-Jun; Ahmad, Faiyaz; Philp, Andrew; Baar, Keith; Williams, Tishan; Luo, Haibin; Ke, Hengming; Rehmann, Holger; Taussig, Ronald; Brown, Alexandra L; Kim, Myung K; Beaven, Michael A; Burgin, Alex B; Manganiello, Vincent; Chung, Jay H

2012-02-03

Resveratrol, a polyphenol in red wine, has been reported as a calorie restriction mimetic with potential antiaging and antidiabetogenic properties. It is widely consumed as a nutritional supplement, but its mechanism of action remains a mystery. Here, we report that the metabolic effects of resveratrol result from competitive inhibition of cAMP-degrading phosphodiesterases, leading to elevated cAMP levels. The resulting activation of Epac1, a cAMP effector protein, increases intracellular Ca(2+) levels and activates the CamKKβ-AMPK pathway via phospholipase C and the ryanodine receptor Ca(2+)-release channel. As a consequence, resveratrol increases NAD(+) and the activity of Sirt1. Inhibiting PDE4 with rolipram reproduces all of the metabolic benefits of resveratrol, including prevention of diet-induced obesity and an increase in mitochondrial function, physical stamina, and glucose tolerance in mice. Therefore, administration of PDE4 inhibitors may also protect against and ameliorate the symptoms of metabolic diseases associated with aging. Copyright © 2012 Elsevier Inc. All rights reserved.

Effects of sodium benzoate on pre-pulse inhibition deficits and hyperlocomotion in mice after administration of phencyclidine.

PubMed

Matsuura, Akiko; Fujita, Yuko; Iyo, Masaomi; Hashimoto, Kenji

2015-06-01

A recent clinical study demonstrated that sodium benzoate (SB), a prototype competitive d-amino acid oxidase inhibitor, was effective in the treatment of several symptoms, such as positive and negative symptoms, and cognitive impairment in medicated patients with schizophrenia. The objective of the study was to examine the effects of SB on behavioural abnormalities such as pre-pulse inhibition (PPI) deficits and hyperlocomotion in mice after a single administration of the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP). The effects of SB on behavioural abnormalities (PPI deficits and hyperlocomotion) in mice after PCP administration were examined. Furthermore, effects of SB on tissue levels of amino acids were also examined. A single oral dose of SB (100, 300, or 1000 mg/kg) attenuated PPI deficits in mice after administration of PCP (3.0 mg/kg, s.c.) in a dose-dependent manner. In contrast, L-701,324 (10 mg/kg), an antagonist at the glycine site of the NMDA receptor, did not affect the effect of SB (1000 mg/kg) on PCP-induced PPI deficits. Furthermore, a single oral dose of SB (1000 mg/kg) significantly attenuated the hyperlocomotion in mice after administration of PCP (3.0 mg/kg, s.c.). However, a single oral dose of SB (1000 mg/kg) caused no changes to D-serine levels in plasma or in the frontal cortex, hippocampus, and striatum of these animals. This study suggests that SB induced antipsychotic effects in the PCP model of schizophrenia, although it did not increase D-serine levels in the brain.

Mesenchymal stem cell-derived microparticles ameliorate peritubular capillary rarefaction via inhibition of endothelial-mesenchymal transition and decrease tubulointerstitial fibrosis in unilateral ureteral obstruction.

PubMed

Choi, Hoon Young; Lee, Hyun Gyu; Kim, Beom Seok; Ahn, Sun Hee; Jung, Ara; Lee, Mirae; Lee, Jung Eun; Kim, Hyung Jong; Ha, Sung Kyu; Park, Hyeong Cheon

2015-03-11

Microparticles (MPs) derived from kidney-derived mesenchymal stem cells (KMSCs) have recently been reported to ameliorate rarefaction of peritubular capillaries (PTC) in ischemic kidneys via delivery of proangiogenic effectors. This study aimed to investigate whether KMSC-derived MPs show anti-fibrotic effects by ameliorating endothelial-to-mesenchymal transition (EndoMT) in human umbilical vein endothelial cells (HUVEC) in vitro and by preserving PTC in kidneys with unilateral ureteral obstruction (UUO) in vivo. MPs isolated from the supernatants of KMSC were co-cultured with HUVEC to assess their in vitro biologic effects on endothelial cells. Mice were treated with MPs via the tail vein after UUO injury to assess their anti-fibrotic and PTC sparing effects. Renal tubulointerstitial damage and inflammatory cell infiltration were examined with Masson's trichrome, F4/80 and α-smooth muscle actin (α-SMA) staining and PTC rarefaction index was determined by CD31 staining. KMSC-derived MPs significantly ameliorated EndoMT and improved in vitro proliferation of TGF-β1 treated HUVEC. In vivo administration of KMSC-derived MPs significantly inhibited EndoMT of PTC endothelial cells and improved PTC rarefaction in UUO kidneys. Furthermore, administration of KMSC-derived MPs inhibited inflammatory cell infiltration as well as tubulointerstitial fibrosis in UUO mice as demonstrated by decreased F4/80 and α-SMA-positive cells and Masson's trichrome staining, respectively. Our results suggest that KMSC-derived MPs ameliorate PTC rarefaction via inhibition of EndoMT and protect against progression of renal damage by inhibiting tubulointerstitial fibrosis.

Acute treatment with cannabinoid receptor agonist WIN55212.2 improves prepulse inhibition in psychosocially stressed mice.

PubMed

Brzózka, Magdalena M; Fischer, André; Falkai, Peter; Havemann-Reinecke, Ursula

2011-04-15

Cannabis, similar to psychosocial stress, is well known to exacerbate psychotic experiences and can precipitate psychotic episodes in vulnerable individuals. Cannabinoid receptors 1 (CB1) are widely expressed in the brain and are particularly important to mediate the effects of cannabis. Chronic cannabis use in patients and chronic cannabinoids treatment in animals is known to cause reduced prepulse inhibition (PPI). Similarly, chronic psychosocial stress in mice impairs PPI. In the present study, we investigated the synergistic effects of substances modulating the CB1-receptors and chronic psychosocial stress on PPI. For this purpose, adult C57Bl/6J mice were exposed to chronic psychosocial stress using the resident-intruder paradigm. The cannabinoid receptor agonist WIN55212.2 served as a surrogate marker for the effects of cannabis in the brain. After exposure to stress mice were acutely injected with WIN55212.2 (3 mg/kg) with or without pre-treatment with Rimonabant (3 mg/kg), a specific CB1-receptor antagonist, and subjected to behavioral testing. Stressed mice displayed a higher vulnerability to WIN55212.2 in the PPI test than control animals. The effects of WIN55212.2 on PPI were antagonized by Rimonabant suggesting an involvement of CB1-receptors in sensorimotor gating. Interestingly, WIN55212.2 increased PPI in psychosocially stressed mice although previous studies in rats showed the opposite effects. It may thus be possible, that depending on the doses of cannabinoids/CB1-receptor agonists applied and environmental conditions (psychosocial stress), opposite effects can be evoked in different experimental animals. Taken together, our data imply that CB1-receptors might play a crucial role in the synergistic effects of psychosocial stress and cannabinoids in brain. Copyright © 2010 Elsevier B.V. All rights reserved.

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. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Somatostatin-28 modulates prepulse inhibition of the acoustic startle response, reward processes and spontaneous locomotor activity in rats

PubMed Central

Semenova, Svetlana; Hoyer, Daniel; Geyer, Mark A.; Markou, Athina

2011-01-01

Somatostatins have been shown to be involved in the pathophysiology of motor and affective disorders, as well as psychiatry disorders, including schizophrenia. We hypothesized that in addition to motor function, somatostatin may be involved in somatosensory gating and reward processes that have been shown to be dysregulated in schizophrenia. Accordingly, we evaluated the effects of intracerebroventricular administration of somatostatin-28 on spontaneous locomotor and exploratory behavior measured in a behavioral pattern monitor, sensorimotor gating, prepulse inhibition (PPI) of the acoustic startle reflex, and brain reward function (measured in a discrete trial intracranial self-stimulation procedure) in rats. Somatostatin-28 decreased spontaneous locomotor activity during the first 10 min of a 60 min testing session with no apparent changes in the exploratory activity of rats. The highest somatostatin-28 dose (10 μg/5 μl/side) induced PPI deficits with no effect on the acoustic startle response or startle response habituation. The somatostatin-induced PPI deficit was partially reversed by administration of SRA-880, a selective somatostatin 1 (sst1) receptor antagonist. Somatostatin-28 also induced elevations in brain reward thresholds, reflecting an anhedonic-like state. SRA-880 had no effect on brain reward function under baseline conditions. Altogether these findings suggest that somatostatin-28 modulates PPI and brain reward function but does not have a robust effect on spontaneous exploratory activity. Thus, increases in somatostatin transmission may represent one of the neurochemical mechanisms underlying anhedonia, one of the negative symptoms of schizophrenia, and sensorimotor gating deficits associated with cognitive impairments in schizophrenia patients. PMID:20537385

Modulation of prepulse inhibition through both M1 and M4 muscarinic receptors in mice

PubMed Central

Thomsen, Morgane; Wess, Jürgen; Fulton, Brian S.; Fink-Jensen, Anders; Caine, S. Barak

2014-01-01

Rationale Muscarinic cholinergic M1 and M4 receptors may participate in schizophrenia's etiology, and have been proposed as targets for antipsychotic medications. Objective Here we investigated the involvement of these receptors in behavioral measures pertinent to schizophrenia using knockout mice lacking M1 receptors (M1−/−), M4 receptors (M4−/−) or both (M1−/−M4−/−). Methods We measured prepulse inhibition of startle (PPI) without drugs, and after treatment with scopolamine (0.32–1.8 mg/kg), xanomeline (3.2 mg/kg) oxotremorine (0.032–0.1 mg/kg), clozapine (1.0–5.6 mg/kg), or haloperidol (0.32–3.2 mg/kg). Results In female (but not male) mice, combined deletion of both M1 and M4 receptors decreased PPI relative to wild-type mice, while knockout of either receptor alone had no significant effect. Scopolamine disrupted PPI in wild-type and M4−/− mice, but not in female M1−/−M4−/− or female M1−/− mice. When administered before scopolamine, xanomeline restored PPI in wild-type mice and M1−/− mice, but not in M4−/− mice. In contrast, pretreatment with oxotremorine increased PPI regardless of genotype. Effects of clozapine and haloperidol on PPI were not hindered by either mutation. Conclusions Deletion of both M1 and M4 receptors can disrupt PPI, suggesting that (at least partially redundant) M1 and M4 receptor-dependent functions are involved in sensorimotor gating mechanisms. PPI-disrupting effects of muscarinic antagonists appeared dependent upon M1 receptor blockade. Our data also suggest that xanomeline exerts antipsychotic-like effects mainly through M4 receptor stimulation, while stimulation of non-M1/M4 subtypes may also have antipsychotic potential. Finally, our results do not support a role of M1/M4 receptors in mediating antipsychotic-like effects of clozapine. PMID:20013114

Mangiferin ameliorates insulin resistance by inhibiting inflammation and regulatiing adipokine expression in adipocytes under hypoxic condition.

PubMed

Yang, Chao-Qiang; Xu, Jing-Hua; Yan, Dan-Dan; Liu, Bao-Lin; Liu, Kang; Huang, Fang

2017-09-01

Adipose tissue hypoxia has been recognized as the initiation of insulin resistance syndromes. The aim of the present study was to investigate the effects of mangiferin on the insulin signaling pathway and explore whether mangiferin could ameliorate insulin resistance caused by hypoxia in adipose tissue. Differentiated 3T3-L1 adipocytes were incubated under normal and hypoxic conditions, respectively. Protein expressions were analyzed by Western blotting. Inflammatory cytokines and HIF-1-dependent genes were tested by ELISA and q-PCR, respectively. The glucose uptake was detected by fluorescence microscopy. HIF-1α was abundantly expressed during 8 h of hypoxic incubation. Inflammatory reaction was activated by up-regulated NF-κB phosphorylation and released cytokines like IL-6 and TNF-α. Glucose uptake was inhibited and insulin signaling pathway was damaged as well. Mangiferin substantially inhibited the expression of HIF-1α. Lactate acid and lipolysis, products released by glycometabolism and lipolysis, were also inhibited. The expression of inflammatory cytokines was significantly reduced and the damaged insulin signaling pathway was restored to proper functional level. The glucose uptake of hypoxic adipocytes was promoted and the dysfunction of adipocytes was relieved. These results showed that mangiferin could not only improve the damaged insulin signaling pathway in hypoxic adipocytes, but also ameliorate inflammatory reaction and insulin resistance caused by hypoxia. Copyright © 2017 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Use of pre-pulse in laser spot welding of materials with high optical reflection

NASA Astrophysics Data System (ADS)

Mys, Ihor; Geiger, Manfred

2003-11-01

Laser micro welding has become a standard manufacturing technique, particularly in industry sectors, such as automotive and aerospace electronics or medical devices, where the requirements for strength, miniaturization and temperature resistance are constantly rising. So far the use of laser micro welding is limited due to the fluctuation of the quality of the welded joints, because the welding results for material with high optical reflection and thermal conductivity, such as copper and copper alloys, depend very strongly on the condition of the material surface. This paper presents investigations on the use of a laser pre-pulse in spot welding of electronic materials with Nd:YAG laser. In order to achieve reproducible joining results two strategies are followed-up. The first one utilizes a reflection-based process control for measuring the reflection during the short pre-pulse. The intensity of the reflected light is used to calculate an appropriated welding pulse power, which corresponds to the measured relative absorption. Adjustment of laser parameters according to the condition of the surface is done in real time before laser main pulse. A second possibility for the stabilization of copper welding is the employment of a short and powerful laser pre-pulse before laser main pulse. This pre-pulse affects the workpiece surface and creates more reproducible absorption conditions for the main pulse, independent from the initial situation on material surface.

Sensorimotor Gating in Depressed and Euthymic Patients with Bipolar Disorder: Analysis on Prepulse Inhibition of Acoustic Startle Response Stratified by Gender and State.

PubMed

Matsuo, Junko; Ota, Miho; Hidese, Shinsuke; Teraishi, Toshiya; Hori, Hiroaki; Ishida, Ikki; Hiraishi, Moeko; Kunugi, Hiroshi

2018-01-01

Prepulse inhibition (PPI) of the acoustic startle reflex is an operational measure of sensorimotor gating. The findings on PPI deficits in bipolar disorder (BD) are inconsistent among studies due to various confounding factors such as gender. This study aimed to assess sensorimotor gating deficits in patients with BD stratified by gender and state (depressed/euthymic), and to explore related clinical variables. Subjects were 106 non-manic BD patients (26 BD I and 80 BD II; 63 with depression and 43 euthymic) and 232 age-, gender-, and ethnicity-matched (Japanese) healthy controls. Depression severity was assessed using the Hamilton Depression Rating Scale-21. The electromyographic activity of the orbicularis oculi muscle was measured by a computerized startle reflex test unit. Startle magnitude, habituation, and PPI were compared among the three clinical groups: depressed BD, euthymic BD, and healthy controls. In a second analysis, patients were divided into four groups using the quartile PPI levels of controls of each gender, and a ratio of the low-PPI group (<1st quartile of controls) was compared. Effects of psychosis and medication status were examined by the Mann-Whitney U test. Clinical correlates such as medication dosage and depression severity with startle measurements were examined by Spearman's correlation. Male patients with depression, but not euthymic male patients, showed significantly lower PPI at a prepulse of 86 dB and 120 ms lead interval than did male controls. More than half of the male patients with depression showed low-PPI. In contrast, PPI in female patients did not differ from that in female controls in either the depressed or euthymic state. Female patients with active psychosis showed significantly lower PPI than those without psychosis. Female patients on typical antipsychotics had significantly lower PPI, than those without such medication. PPI showed a significant positive correlation with lamotrigine dosage in male patients and

Plumbagin, a vitamin K3 analogue ameliorate malaria pathogenesis by inhibiting oxidative stress and inflammation.

PubMed

Gupta, Amit Chand; Mohanty, Shilpa; Saxena, Archana; Maurya, Anil Kumar; Bawankule, Dnyaneshwar U

2018-03-22

Plumbagin, a vitamin K3 analogue is the major active constituent in several plants including root of Plumbago indica Linn. This compound has been shown to exhibit a wide spectrum of pharmacological activities. The present investigation was to evaluate the ameliorative effects of plumbagin (PL) against severe malaria pathogenesis due to involvement of oxidative stress and inflammatory response in Plasmodium berghei infected malaria in mice. Malaria pathogenesis was induced by intra-peritoneal injection of P. berghei infected red blood cells into the Swiss albino mice. PL was administered orally at doses of 3, 10 and 30 mg/kg/day following Peter's 4 day suppression test. Oral administration of PL showed significant reduction of parasitaemia and increase in mean survival time. PL treatment is also attributed to significant increase in the blood glucose and haemoglobin level when compared with vehicle-treated infected mice. Significant inhibition in level of oxidative stress and pro-inflammation related markers were observed in PL treated group. The trend of inhibition in oxidative stress markers level after oral treatment of PL was MPO > LPO > ROS in organ injury in P. berghei infected mice. This study showed that plumbagin is able to ameliorate malaria pathogenesis by augmenting anti-oxidative and anti-inflammatory mechanism apart from its effect on reducing parasitaemia and increasing mean survival time of malaria-induced mice.

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. Copyright © 2014. Published by Elsevier Inc.

Ghrelin Ameliorates Asthma by Inhibiting Endoplasmic Reticulum Stress.

PubMed

Fu, Tian; Wang, Lei; Zeng, Qingdi; Zhang, Yan; Sheng, Baowei; Han, Liping

2017-12-01

This study aimed to confirm the ameliorative effect of ghrelin on asthma and investigate its mechanism. The murine model of asthma was induced by ovalbumin (OVA) treatment and assessed by histological pathology and airway responsiveness to methacholine. The total and differential leukocytes were counted. Tumor necrosis factor α, interferon γ, interleukin-5 and interleukin-13 levels in bronchoalveolar lavage fluid were quantified by commercial kits. The protein levels in pulmonary tissues were measured by Western blot analysis. Ghrelin ameliorated the histological pathology and airway hyperresponsiveness in the OVA-induced asthmatic mouse model. Consistently, OVA-increased total and differential leukocytes and levels of tumor necrosis factor α, interferon γ, interleukin-5 and interleukin-13 in bronchoalveolar lavage fluid were significantly attenuated by ghrelin. Ghrelin prevented the increased protein levels of the endoplasmic reticulum stress markers glucose regulated protein 78 and CCAAT/enhancer binding protein homologous protein and reversed the reduced levels of p-Akt in asthmatic mice. Ghrelin might prevent endoplasmic reticulum stress activation by stimulating the Akt signaling pathway, which attenuated inflammation and ameliorated asthma in mice. Ghrelin might be a new target for asthma therapy. Copyright © 2017. Published by Elsevier Inc.

The influence of prepulse level on the 3p-3s XUV laser output from Ne-like ions of Zn, Cu and Ni

NASA Astrophysics Data System (ADS)

MacPhee, A. G.; Lewis, C. L. S.; Warwick, P. J.; Weaver, I.; Jaeglé, P.; Carillon, A.; Jamelot, G.; Klisnick, A.; Rus, B.; Zeitoun, Ph.; Nantel, M.; Goedkindt, P.; Sebban, S.; Tallents, G. J.; Demir, A.; Holden, M.; Krishnan, J.

1997-02-01

We have studied the effect of prepulses in enhancing the efficiency of generating ASE beams in soft X-ray laser plasma amplifiers based on pumping Ne-like ions. Slab targets were irradiated with a weak prepulse followed by a main plasma heating pulse of nanosecond duration. Time-integrated: time and spectrally resolved and time and angularly resolved lasing emissions on the 3p-3s ( J = 0-1) XUV lasing lines of Ne-like Ni, Cu and Zn at wavelengths 232 Å, 221 Å and 212 Å respectively have been monitored. Measurements were made for pre-pulse/main-pulse intensity ratios from 10 -5-10 -1 and for pump delay times of 2 ns and 4.5 ns. Zinc is shown to exhibit a peak in output intensity at ˜ 2 × 10 -3 pre-pulse fraction for a 4.5 ns pump delay, with a main pulse pump intensity of ˜ 1.3 × 10 13W cm -2 on a 20 mm target. The Zn lasing emission had a duration of ˜ 240 ps and this was insensitive to prepulse fraction. The J = 0-1 XUV laser output for nickel and copper increased monotonically with prepulse fraction, with copper targets showing least sensitivity to either prepulse level or prepulse to main pulse delay. Under the conditions of the study, the pre-pulse level was observed to have no significant influence on the output intensity of the 3p-3s ( J = 2-1) lines of any of the elements investigated.

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. © 2016 Wiley Periodicals, Inc.

Inhibition of thrombin action ameliorates insulin resistance in type 2 diabetic db/db mice.

PubMed

Mihara, Masatomo; Aihara, Ken-ichi; Ikeda, Yasumasa; Yoshida, Sumiko; Kinouchi, Mizuho; Kurahashi, Kiyoe; Fujinaka, Yuichi; Akaike, Masashi; Matsumoto, Toshio

2010-02-01

The binding of thrombin to its receptor stimulates inflammatory cytokines including IL-6 and monocyte chemoattractant protein-1 (MCP-1); both are associated with the development of insulin resistance. Because increased adiposity enhanced the expression of coagulation factor VII that stimulates the coagulation pathway in adipose tissue, we tested whether the inhibition of thrombin action ameliorates insulin resistance in obese diabetic (Lpr(-/-):db/db) mice. The 4-wk administration of argatroban, a selective thrombin inhibitor, reduced fasting plasma glucose and ameliorated insulin resistance in these mice. It also reduced adipocyte size and macrophage infiltration into adipose tissue. The aberrant gene expression of MCP-1, IL-6, adiponectin, and factor VII and suppressed insulin receptor substrate-1-Akt signaling in adipose tissue of db/db mice were reversed by argatroban treatment. These results demonstrate that increased adiposity enhances the production of thrombin in adipose tissue by stimulating factor VII expression and suggest that increased thrombin activity in adipose tissue plays an important role in the development of insulin resistance via enhancing MCP-1 production, leading to macrophage infiltration and insulin receptor substrate-1-Akt pathway inactivation.

Preventive effect of α-lipoic acid on prepulse inhibition deficits in a juvenile two-hit model of schizophrenia.

PubMed

Deslauriers, J; Racine, W; Sarret, P; Grignon, S

2014-07-11

Some pathophysiological models of schizophrenia posit that prenatal inflammation sensitizes the developing brain to second insults in early life and enhances brain vulnerability, thereby increasing the risk of developing the disorder during adulthood. We previously developed a two-hit animal model, based on the well-established prenatal immune challenge with poly-inosinic/cytidylic acid (polyI:C), followed by juvenile restraint stress (RS). We observed an additive disruption of prepulse inhibition (PPI) of acoustic startle in juvenile mice submitted to both insults. Previous studies have also reported that oxidative stress is associated with pathophysiological mechanisms of psychiatric disorders, including schizophrenia. We report here that PPI disruption in our two-hit animal model of schizophrenia is associated with an increase in oxidative stress. These findings led us to assess whether α-lipoic acid, an antioxidant, can prevent both increase in oxidative status and PPI deficits in our juvenile in vivo model of schizophrenia. In the offspring submitted to prenatal injection of polyI:C and to RS, treatment with α-lipoic acid prevented the development of PPI deficits 24h after the last period of RS. α-Lipoic acid also improved PPI performance in control mice. The reversal effect of α-lipoic acid pretreatment on these behavioral alterations was further accompanied by a normalization of the associated oxidative status and dopaminergic and GABAergic abnormalities in the prefrontal cortex. Based on our double insult paradigm, these results support the hypothesis that oxidative stress plays an important role in the development of PPI deficits, a well-known behavior associated with schizophrenia. These findings form the basis of future studies aiming to unravel mechanistic insights of the putative role of antioxidants in the treatment of schizophrenia, especially during the prodromal stage. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Inhibition of interleukin-6 decreases atrogene expression and ameliorates tail suspension-induced skeletal muscle atrophy

PubMed Central

Yakabe, Mitsutaka; Ota, Hidetaka; Iijima, Katsuya; Eto, Masato; Ouchi, Yasuyoshi; Akishita, Masahiro

2018-01-01

Background Interleukin-6 (IL-6) is an inflammatory cytokine. Whether systemic IL-6 affects atrogene expression and disuse-induced skeletal muscle atrophy is unclear. Methods Tail-suspended mice were used as a disuse-induced muscle atrophy model. We administered anti-mouse IL-6 receptor antibody, beta-hydroxy-beta-methylbutyrate (HMB) and vitamin D to the mice and examined the effects on atrogene expression and muscle atrophy. Results Serum IL-6 levels were elevated in the mice. Inhibition of IL-6 receptor suppressed muscle RING finger 1 (MuRF1) expression and prevented muscle atrophy. HMB and vitamin D inhibited the serum IL-6 surge, downregulated the expression of MuRF1 and atrogin-1 in the soleus muscle, and ameliorated atrophy in the mice. Conclusion Systemic IL-6 affects MuRF1 expression and disuse-induced muscle atrophy. PMID:29351340

Contrast degradation in a chirped-pulse amplifier due to generation of prepulses by postpulses.

PubMed

Didenko, N V; Konyashchenko, A V; Lutsenko, A P; Tenyakov, S Yu

2008-03-03

Experiment and modeling show that the refractive index nonlinearity can significantly degrade the contrast of a chirped-pulse amplifier seeded with a pulse and a single postpulse. Multiple powerful non-equidistant pre- and postpulses are generated. For a Gaussian pulse and a hat-top beam, an incident postpulse of energy W results in a prepulse of energy 0.58B(2)W, where B is the nonlinear phase (B-integral) of the main pulse. Calculations show that level of satellites due to gain saturation is negligibly small. Experimental results for Ti:Sapphire regenerative and multipass amplifiers and prepulse generation in fused silica agree well with the theory.

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

PubMed

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

2014-02-01

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. 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. 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). 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.

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

PubMed Central

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

2016-01-01

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

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

PubMed

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

2016-05-10

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

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. Copyright © 2015 the American Physiological Society.

Dominant-negative inhibition of Ca2+ influx via TRPV2 ameliorates muscular dystrophy in animal models.

PubMed

Iwata, Yuko; Katanosaka, Yuki; Arai, Yuji; Shigekawa, Munekazu; Wakabayashi, Shigeo

2009-03-01

Muscular dystrophy is a severe degenerative disorder of skeletal muscle characterized by progressive muscle weakness. One subgroup of this disease is caused by a defect in the gene encoding one of the components of the dystrophin-glycoprotein complex, resulting in a significant disruption of membrane integrity and/or stability and, consequently, a sustained increase in the cytosolic Ca(2+) concentration ([Ca(2+)](i)). In the present study, we demonstrate that muscular dystrophy is ameliorated in two animal models, dystrophin-deficient mdx mice and delta-sarcoglycan-deficient BIO14.6 hamsters by dominant-negative inhibition of the transient receptor potential cation channel, TRPV2, a principal candidate for Ca(2+)-entry pathways. When transgenic (Tg) mice expressing a TRPV2 mutant in muscle were crossed with mdx mice, the [Ca(2+)](i) increase in muscle fibers was reduced by dominant-negative inhibition of endogenous TRPV2. Furthermore, histological, biochemical and physiological indices characterizing dystrophic pathology, such as an increased number of central nuclei and fiber size variability/fibrosis/apoptosis, elevated serum creatine kinase levels, and reduced muscle performance, were all ameliorated in the mdx/Tg mice. Similar beneficial effects were also observed in the muscles of BIO14.6 hamsters infected with adenovirus carrying mutant TRPV2. We propose that TRPV2 is a principal Ca(2+)-entry route leading to a sustained [Ca(2+)](i) increase and muscle degeneration, and that it is a promising therapeutic target for the treatment of muscular dystrophy.

Quercetin ameliorates pulmonary fibrosis by inhibiting SphK1/S1P signaling.

PubMed

Zhang, Xingcai; Cai, Yuli; Zhang, Wei; Chen, Xianhai

2018-06-25

Idiopathic pulmonary fibrosis (IPF) is an agnogenic chronic disorder with high morbidity and low survival rate. Quercetin is a flavonoid found in a variety of herbs with anti-fibrosis function. In this study, bleomycin was employed to induce a pulmonary fibrosis mouse model. The quercetin administration ameliorated bleomycin-induced pulmonary fibrosis, evidenced by the expression level changes of hydroxyproline, fibronectin, α-smooth muscle actin, Collagen I and Collagen III. The similar results were observed in transforming growth factor (TGF)-β-treated human embryonic lung fibroblast (HELF). The bleomycin or TGF-β administration caused the increase of sphingosine-1-phosphate (S1P) level in pulmonary tissue and HELF cells, as well as its activation-required kinase, sphingosine kinase 1 (SphK1), and its degradation enzyme, sphinogosine-1-phosphate lyase (S1PL). However, the increase of S1P, SphK1 and S1PL was attenuated by application of quercetin. In addition, the effect of quercetin on fibrosis was abolished by the ectopic expression of SphK1. The colocalization of SphK1/S1PL and fibroblast specific protein 1 (FSP1) suggested the roles of fibroblasts in pulmonary fibrosis. In summary, we demonstrated that quercetin ameliorated pulmonary fibrosis in vivo and in vitro by inhibiting SphK1/S1P signaling.

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.

Genetic inhibition of JNK3 ameliorates spinal muscular atrophy.

PubMed

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

2015-12-15

Mutation of the Survival Motor Neuron 1 (SMN1) gene causes spinal muscular atrophy (SMA), an autosomal recessive neurodegenerative disorder that occurs in early childhood. Degeneration of spinal motor neurons caused by SMN deficiency results in progressive muscle atrophy and death in SMA. The molecular mechanism underlying neurodegeneration in SMA is unknown. No treatment is available to prevent neurodegeneration and reduce the burden of illness in SMA. We report that the c-Jun NH2-terminal kinase (JNK) signaling pathway mediates neurodegeneration in SMA. The neuron-specific isoform JNK3 is required for neuron degeneration caused by SMN deficiency. JNK3 deficiency reduces degeneration of cultured neurons caused by low levels of SMN. Genetic inhibition of JNK pathway in vivo by Jnk3 knockout results in amelioration of SMA phenotype. JNK3 deficiency prevents the loss of spinal cord motor neurons, reduces muscle degeneration, improves muscle fiber thickness and muscle growth, improves motor function and overall growth and increases lifespan of mice with SMA that shows a systemic rescue of phenotype by a SMN-independent mechanism. JNK3 represents a potential (non-SMN) therapeutic target for the treatment of SMA. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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

NASA Astrophysics Data System (ADS)

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

2008-01-01

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 140mm and maximum current from 3.5to5MA. 700to800ns implosion Z-pinch experiments are performed on this driver essentially with aluminium. Best results obtained before the improvement described in this paper were 1-3TW radial total power, 100-300kJ total yield, and 20-30kJ energy above 1keV. 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 ˜10kA and 50μs. 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.

Tea polysaccharide inhibits RANKL-induced osteoclastogenesis in RAW264.7 cells and ameliorates ovariectomy-induced osteoporosis in rats.

PubMed

Xu, Huanhuan; Yin, Dan; Liu, Titi; Chen, Fei; Chen, Yingli; Wang, Xuanjun; Sheng, Jun

2018-06-01

Tea drinking has positive effects on bone health and may prevent and treat osteoporosis, especially in older and postmenopausal women. Tea polysaccharide (TPS) is a major bioactive constituent in tea. Despite its profound effects on human health, whether TPS has anti-osteoporotic effects remains largely unknown. As such, we investigated the anti-osteoporotic effects of TPS. In vitro, TPS effects on osteoclastogenesis were examined using osteoclast precursor RAW264.7 cells. TPS effects on osteoclastogenesis-related expression of marker genes and proteins were determined by gene expression and immunoblotting analyses, respectively. For in vivo studies, 12-week-old female Wistar rats were divided randomly into a sham-operated group (sham) and four ovariectomized (OVX) subgroups: OVX with vehicle (model) and OVX with low-, medium-, and high-dose TPS (0.32, 0.64 and 1.28 g/kg body weight/day, respectively). TPS was administered intragastrically to rats for 13 weeks. Body weight, blood biochemical parameters, organ weight, organ coefficients, femoral length, bone mineral density (BMD), biomechanical properties, and bone microarchitecture were documented. TPS inhibited osteoclast differentiation significantly and dose-dependently, and its inhibitory effect was not due to toxicity to RAW264.7 cells. TPS suppressed expression of osteoclastogenesis-related marker genes and proteins significantly. In in vivo studies, medium-dose TPS treatment ameliorated OVX-induced calcium loss significantly. Low-dose TPS treatment decreased the activity of acid phosphatase (ACP) in OVX rats significantly. In addition, TPS treatment improved other blood biochemical parameters and femoral biomechanical properties to a certain extent. More importantly, TPS treatment ameliorated bone microarchitecture in OVX rats strikingly because of increased cortical bone thickness and trabecular bone area in the femur. TPS can inhibit receptor activator nuclear factor-kappa B ligand (RANKL

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

Effects of cannabinoid drugs on the deficit of prepulse inhibition of startle in an animal model of schizophrenia: the SHR strain.

PubMed

Levin, Raquel; Peres, Fernanda F; Almeida, Valéria; Calzavara, Mariana B; Zuardi, Antonio W; Hallak, Jaime E C; Crippa, José Alexandre S; Abílio, Vanessa C

2014-01-01

Clinical and neurobiological findings suggest that the cannabinoids and the endocannabinoid system may be implicated in the pathophysiology and treatment of schizophrenia. We described that the spontaneously hypertensive rats (SHR) strain presents a schizophrenia behavioral phenotype that is specifically attenuated by antipsychotic drugs, and potentiated by proschizophrenia manipulations. Based on these findings, we have suggested this strain as an animal model of schizophrenia. The aim of this study was to evaluate the effects of cannabinoid drugs on the deficit of prepulse inhibition (PPI) of startle, the main paradigm used to study sensorimotor gating impairment related to schizophrenia, presented by the SHR strain. The following drugs were used: (1) WIN55212,2 (cannabinoid agonist), (2) rimonabant (CB1 antagonist), (3) AM404 (anandamide uptake inhibitor), and (4) cannabidiol (CBD; indirect CB1/CB2 receptor antagonist, among other effects). Wistar rats (WRs) and SHRs were treated with vehicle (VEH) or different doses of WIN55212 (0.3, 1, or 3 mg/kg), rimonabant (0.75, 1.5, or 3 mg/kg), AM404 (1, 5, or 10 mg/kg), or CBD (15, 30, or 60 mg/kg). VEH-treated SHRs showed a decreased PPI when compared to WRs. This PPI deficit was reversed by 1 mg/kg WIN and 30 mg/kg CBD. Conversely, 0.75 mg/kg rimonabant decreased PPI in SHR strain, whereas AM404 did not modify it. Our results reinforce the role of the endocannabinoid system in the sensorimotor gating impairment related to schizophrenia, and point to cannabinoid drugs as potential therapeutic strategies.

Korean red ginseng ameliorated experimental pancreatitis through the inhibition of hydrogen sulfide in mice.

PubMed

Lee, Sooyeon; Park, Jong-Min; Jeong, Migyeong; Han, Young-Min; Go, Eun Jin; Ko, Weon Jin; Cho, Joo Young; Kwon, Chang Il; Hahm, Ki Baik

2016-01-01

Effective therapy to treat acute pancreatitis (AP) or to prevent its recurrence/complication is still not available. Based on previous results that suggest that: i) hydrogen sulfide (H2S) levels were significantly increased in pancreatitis and gastritis and ii) Korean red ginseng (KRG) efficiently attenuated Helicobacter pylori-associated gastritis through the suppressive actions of H2S, we hypothesized that KRG can ameliorate experimental pancreatitis through suppression of H2S generation. C57BL/6 mice were pre-administered KRG and then subjected to cerulein injection or pancreatic duct ligation (PDL) to induce pancreatitis. Blood and pancreas tissues were collected and processed to measure serum levels of amylase, lipase and myeloperoxidase and the concentration of H2S and the levels of various inflammatory cytokine in pancreatic tissues of mice with induced AP. KRG significantly inhibited NaHS-induced COX-2 and TNF-α mRNA in pancreatic cells, but dl-propargylglycine did not. KRG ameliorated cerulein-induced edematous pancreatitis accompanied with significant inactivation of NF-κB and JNK in pancreatic tissues of C57BL/6 mice (p < 0.001) and also significantly ameliorated PDL-induced necrotizing pancreatitis (p<0.01); in both conditions, the significant suppression of H2S resulting from KRG pretreatment afforded rescuing outcomes. Along with suppressed levels of H2S consequent to depressed expressions of CBS and CSE mRNA, KRG administration efficiently decreased the serum level of amylase, lipase, and myeloperoxidase and the expression of inflammatory cytokines in animal models of mild or severe AP. These results provide evidence for the preventive and therapeutic roles of KRG against AP mediated by H2S suppression. Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.

Carnosine ameliorates lens protein turbidity formations by inhibiting calpain proteolysis and ultraviolet C-induced degradation.

PubMed

Liao, Jiahn-Haur; Lin, I-Lin; Huang, Kai-Fa; Kuo, Pei-Ting; Wu, Shih-Hsiung; Wu, Tzu-Hua

2014-06-25

Carnosine (CAR) is an endogenous peptide and present in lens, but there is little evidence for its effectiveness in calpain-induced proteolysis inhibition and its differential effects toward different wavelengths of ultraviolet (UV) irradiation. This study aimed to develop three in vitro cataract models to compare the mechanisms underlying the protective activities of CAR. Crude crystallins extracted from porcine lenses were used for antiproteolysis assays, and purified γ-crystallins were used for anti-UV assays. The turbidity in those in vitro models mimics cataract formation and was assayed by measuring optical density (OD) at 405 nm. The effectiveness of CAR on calpain-induced proteolysis was studied at 37 and 58 °C. Patterns of proteins were then analyzed by SDS-PAGE. The turbidity was reduced significantly (p<0.05) at 60 min measurements with the increased concentration of CAR (10-300 mM). SDS-PAGE showed that the decreased intensities at both ∼28 and ∼30 kDa protein bands in heat-enhanced assays were ameliorated by CAR at ≥10 mM concentrations. In UV-B studies, CAR (200, 300 mM) reduced the turbidity of γ-crystallin significantly (p<0.05) at 6 h observations. The turbidity of samples containing γ-crystallins was ameliorated while incubated with CAR (100, 300 mM) significantly (p<0.05) following 4 h of exposure to UV-C. SDS-PAGE showed that the presence of CAR reduced UV-B-induced aggregation of γ-crystallins at ∼44 kDa and resulted in less loss of γ-crystallin following UV-C exposure. The result of modeling also suggests that CAR acts as an inhibitor of calpain. In conclusion, CAR protects lens proteins more readily by inhibiting proteolysis and UV-C-induced degradation than aggregation induced by UV-B irradiation.

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 G 0 /G 1 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. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

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

Inhibition of glycogen synthase kinase 3beta ameliorates triptolide-induced acute cardiac injury by desensitizing mitochondrial permeability transition

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

Wang, Wenwen; Yang, Yanqin; Xiong, Zhewen

Triptolide (TP), a diterpene triepoxide, is a major active component of Tripterygium wilfordii extracts, which are prepared as tablets and has been used clinically for the treatment of inflammation and autoimmune disorders. However, TP's therapeutic potential is limited by severe adverse effects. In a previous study, we reported that TP induced mitochondria dependent apoptosis in cardiomyocytes. Glycogen synthase kinase-3β (GSK-3β) is a multifunctional serine/threonine kinase that plays important roles in the necrosis and apoptosis of cardiomyocytes. Our study aimed to investigate the role of GSK-3β in TP-induced cardiotoxicity. Inhibition of GSK-3β activity by SB 216763, a potent and selective GSK-3more » inhibitor, prominently ameliorated the detrimental effects in C57BL/6J mice with TP administration, which was associated with a correction of GSK-3β overactivity. Consistently, in TP-treated H9c2 cells, SB 216763 treatment counteracted GSK-3β overactivity, improved cell viability, and prevented apoptosis by modulating the expression of Bcl-2 family proteins. Mechanistically, GSK-3β interacted with and phosphorylated cyclophilin F (Cyp-F), a key regulator of mitochondrial permeability transition pore (mPTP). GSK-3β inhibition prevented the phosphorylation and activation of Cyp-F, and desensitized mPTP. Our findings suggest that pharmacological targeting of GSK-3β could represent a promising therapeutic strategy for protecting against cardiotoxicity induced by TP. - Highlights: • GSK-3β inhibition ameliorates TP-induced cardiotoxicity in vitro and in vivo. • GSK-3β controls Cyp-F activation, and regulates mPTP and apoptosis in H9c2 cells. • The protective effect is attributed to GSK-3β activity rather than to protein level. • GSK-3β may be a promising target against TP-induced cardiotoxicity.« less

Spirulina maxima Extract Ameliorates Learning and Memory Impairments via Inhibiting GSK-3β Phosphorylation Induced by Intracerebroventricular Injection of Amyloid-β 1-42 in Mice.

PubMed

Koh, Eun-Jeong; Kim, Kui-Jin; Song, Ji-Hyeon; Choi, Jia; Lee, Hyeon Yong; Kang, Do-Hyung; Heo, Ho Jin; Lee, Boo-Yong

2017-11-13

Spirulina maxima , a microalga containing high levels of protein and many polyphenols, including chlorophyll a and C-phycocyanin, has antioxidant and anti-inflammatory therapeutic effects. However, the mechanisms where by Spirulina maxima ameliorates cognitive disorders induced by amyloid-β 1-42 (Aβ 1-42 ) are not fully understood. In this study, we investigated whether a 70% ethanol extract of Spirulina maxima (SM70EE) ameliorated cognitive impairments induced by an intracerebroventricular injection of Aβ 1-42 in mice. SM70EE increased the step-through latency time in the passive avoidance test and decreased the escape latency time in the Morris water maze test in Aβ 1-42 -injected mice. SM70EE reduced hippocampal Aβ 1-42 levels and inhibited amyloid precursor protein processing-associated factors in Aβ 1-42 -injected mice. Additionally, acetylcholinesterase activity was suppressed by SM70EE in Aβ 1-42 -injected mice. Hippocampal glutathione levels were examined to determine the effects of SM70EE on oxidative stress in Aβ 1-42 -injected mice. SM70EE increased the levels of glutathione and its associated factors that were reduced in Aβ 1-42 -injected mice. SM70EE also promoted activation of the brain-derived neurotrophic factor/phosphatidylinositol-3 kinase/serine/threonine protein kinase signaling pathway and inhibited glycogen synthase kinase-3β phosphorylation. These findings suggested that SM70EE ameliorated Aβ 1-42 -induced cognitive impairments by inhibiting the increased phosphorylation of glycogen synthase kinase-3β caused by intracerebroventricular injection of Aβ 1-42 in mice.

Antipsychotic potential of quinazoline ErbB1 inhibitors in a schizophrenia model established with neonatal hippocampal lesioning.

PubMed

Mizuno, Makoto; Iwakura, Yuriko; Shibuya, Masako; Zheng, Yingjun; Eda, Takeyoshi; Kato, Taisuke; Takasu, Yohei; Nawa, Hiroyuki

2010-01-01

Hyper-signaling of the epidermal growth factor receptor family (ErbB) is implicated in the pathophysiology of schizophrenia. Various quinazoline inhibitors targeting ErbB1 or ErbB2 - 4 have been developed as anti-cancer agents and might be useful for antipsychotic treatment. In the present study, we used an animal model of schizophrenia established by neonatal hippocampal lesioning and evaluated the neurobehavioral consequences of ErbB1-inhibitor treatment. Subchronic administration of the ErbB1 inhibitor ZD1839 to the cerebroventricle of rats receiving neonatal hippocampal lesioning ameliorated deficits in prepulse inhibition as well as those in the latent inhibition of tone-dependent fear learning. There were no apparent adverse effects on basal learning scores or locomotor activity, however. The administration of other ErbB1 inhibitors, PD153035 and OSI-774, similarly attenuated the prepulse inhibition impairment of this animal model. In parallel, there were decreases in ErbB1 phosphorylation in animals treated with ErbB1 inhibitors. These results indicate an antipsychotic potential of quinazoline ErbB1 inhibitors. ErbB receptor tyrosine kinases may be novel therapeutic targets for schizophrenia or its related psychotic symptoms.

Yi-gan san restores behavioral alterations and a decrease of brain glutathione level in a mouse model of schizophrenia.

PubMed

Makinodan, Manabu; Yamauchi, Takahira; Tatsumi, Kouko; Okuda, Hiroaki; Noriyama, Yoshinobu; Sadamatsu, Miyuki; Kishimoto, Toshifumi; Wanaka, Akio

2009-01-01

The traditional Chinese herbal medicine yi-gan san has been used to cure neuropsychological disorders. Schizophrenia can be one of the target diseases of yi-gan san. We aimed at evaluating the possible use of yi-gan san in improving the schizophrenic symptoms of an animal model. Yi-gan san or distilled water was administered to mice born from pregnant mice injected with polyinosinic-polycytidilic acid or phosphate buffered saline. The former is a model of schizophrenia based on the epidemiological data that maternal infection leads to psychotic disorders including schizophrenia in the offspring. Prepulse inhibition and sensitivity to methamphetamine in open field tests were analyzed and the total glutathione content of whole brains was measured. Yi-gan san reversed the decrease in prepulse inhibition, hypersensitivity to methamphetamine and cognitive deficits found in the model mice to the level of control mice. Total glutathione content in whole brains was reduced in the model mice but was restored to normal levels by yi-gan san treatment. These results suggest that yi-gan san may have ameliorating effects on the pathological symptoms of schizophrenia.

Effects of combined exposure to pyridostigmine bromide and shaker stress on acoustic startle response, pre-pulse inhibition and open field behavior in mice.

PubMed

Dubovicky, M; Paton, S; Morris, M; Mach, M; Lucot, J B

2007-01-01

The present study investigated the effect of combined exposure of pyridostigmine bromide (PB) and chronic shaker stress on acoustic startle responses (ASR), pre-pulse inhibition (PPI) and open field behavior of adult C57BL/6J mice. PB (10 mg kg(-1) day(-1) for 7 days) or saline was administered subcutaneously using osmotic Alzet minipumps implanted under the skin on the back of the mice. At the same time, the mice were exposed to 7 days of intermittent shaker stress. They were tested for ASR (100 dB and 120 dB stimuli) and PPI (70 dB + 100 dB and 70 dB + 120 dB) in the acoustic startle monitor system. The mice were assessed during the shaker stress on days 2 and 7 and 7, 14, 21 and 28 days after discontinuation of treatment. Separate groups of mice were tested in the open field in 15 min sessions on days 1, 3 and 6 during shaker stress and PB treatment. Exposure of mice to PB resulted in an exaggerated ASR, reduced PPI and non-significant decrease in locomotor activity. These behavioral changes were apparent only during exposure to PB. Repeated shaker stress did not have any effect on sensorimotor functions or open field behavior of mice. There was no prolonged or delayed effect of PB and/or stress on individual behavioral variables. The study found C57BL/6J mice to be behaviorally sensitive to PB treatment. (c) 2007 John Wiley & Sons, Ltd.

Nicotine blocks apomorphine-induced disruption of prepulse inhibition of the acoustic startle in rats: possible involvement of central nicotinic α7 receptors

PubMed Central

Suemaru, Katsuya; Yasuda, Kayo; Umeda, Kenta; Araki, Hiroaki; Shibata, Kazuhiko; Choshi, Tominari; Hibino, Satoshi; Gomita, Yutaka

2004-01-01

Nicotine has been reported to normalize deficits in auditory sensory gating in the cases of schizophrenia, suggesting an involvement of nicotinic acetylcholine receptors in attentional abnormalities. However, the mechanism remains unclear. The present study investigated the effects of nicotine on the disruption of prepulse inhibition (PPI) of the acoustic startle response induced by apomorphine or phencyclidine in rats. Over the dose range tested, nicotine (0.05–1 mg kg−1, s.c.) did not disrupt PPI. Neither methyllycaconitine (0.5–5 mg kg−1, s.c.), an α7 nicotinic receptor antagonist, nor dihydro-β-erythroidine (0.5–2 mg kg−1, s.c.), an α4β2 nicotinic receptor antagonist, had any effect on PPI. Nicotine (0.01–0.2 mg kg−1, s.c.) dose-dependently reversed the disruption of PPI induced by apomorphine (1 mg kg−1, s.c.), but had no effect on the disruption of PPI induced by phencyclidine (2 mg kg−1, s.c.). The reversal of apomorphine-induced PPI disruption by nicotine (0.2 mg kg−1) was eliminated by mecamylamine (1 mg kg−1, i.p.), but not by hexamethonium (10 mg kg−1, i.p.), indicating the involvement of central nicotinic receptors. The antagonistic action of nicotine on apomorphine-induced PPI disruption was dose-dependently blocked by methyllycaconitine (1 and 2 mg kg−1, s.c.). However, dihydro-β-erythroidine (1 and 2 mg kg−1, s.c.) had no effect. These results suggest that nicotine reverses the disruption of apomorphine-induced PPI through central α7 nicotinic receptors. PMID:15197106

INTRARENAL GHRELIN RECEPTOR INHIBITION AMELIORATES ANGIOTENSIN II-DEPENDENT HYPERTENSION IN RATS.

PubMed

Kemp, Brandon A; Howell, Nancy L; Padia, Shetal H

2018-06-20

The intrarenal ghrelin receptor (GR) is localized to collecting duct (CD) cells where it increases αENaC-dependent sodium reabsorption in rodents. We hypothesized that chronic GR inhibition with intrarenal GR siRNA lowers blood pressure (BP) in Angiotensin II-dependent hypertension via reductions in αENaC-dependent sodium reabsorption. Uninephrectomized Sprague-Dawley rats (N=121) received subcutaneous osmotic pumps for chronic systemic delivery of Angiotensin II or vehicle (5% dextrose in water). Rats also received intrarenal infusion of vehicle, GR siRNA, or scrambled (SCR) siRNA. In rats receiving intrarenal vehicle or intrarenal SCR siRNA, systemic Angiotensin II infusion increased sodium retention and BP on day 1, and BP remained elevated throughout the 5-day study. These rats also demonstrated increased CD GR expression after 5 days of infusion. However, intrarenal GR siRNA infusion prevented Angiotensin II-mediated sodium retention on day 1, induced a continuously negative cumulative sodium balance compared with Angiotensin II alone, and reduced BP chronically. Glomerular filtration rate and renal blood flow remained unchanged in GR siRNA-infused rats. Systemic Angiotensin II infusion also increased serum aldosterone levels, CD αENaC and pSGK1 expression in rats with intrarenal SCR siRNA; however these effects were not observed in the presence of intrarenal GR siRNA, despite exposure to the same systemic Angiotensin II. These data demonstrate that chronic inhibition of intrarenal GR activity significantly reduces αENaC -dependent sodium retention, resulting in a negative cumulative sodium balance, thereby ameliorating Angiotensin II-induced hypertension in rats. Renal GRs represent a novel therapeutic target for the treatment of hypertension and other sodium-retaining states.

Dexamethasone palmitate ameliorates macrophages-rich graft-versus-host disease by inhibiting macrophage functions.

PubMed

Nishiwaki, Satoshi; Nakayama, Takayuki; Murata, Makoto; Nishida, Tetsuya; Terakura, Seitaro; Saito, Shigeki; Kato, Tomonori; Mizuno, Hiroki; Imahashi, Nobuhiko; Seto, Aika; Ozawa, Yukiyasu; Miyamura, Koichi; Ito, Masafumi; Takeshita, Kyosuke; Kato, Hidefumi; Toyokuni, Shinya; Nagao, Keisuke; Ueda, Ryuzo; Naoe, Tomoki

2014-01-01

Macrophage infiltration of skin GVHD lesions correlates directly with disease severity, but the mechanisms underlying this relationship remain unclear and GVHD with many macrophages is a therapeutic challenge. Here, we characterize the macrophages involved in GVHD and report that dexamethasone palmitate (DP), a liposteroid, can ameliorate such GVHD by inhibiting macrophage functions. We found that host-derived macrophages could exacerbate GVHD in a mouse model through expression of higher levels of pro-inflammatory TNF-α and IFN-γ, and lower levels of anti-inflammatory IL-10 than resident macrophages in mice without GVHD. DP significantly decreased the viability and migration capacity of primary mouse macrophages compared to conventional dexamethasone in vitro. DP treatment on day 7 and day 14 decreased macrophage number, and attenuated GVHD score and subsequent mortality in a murine model. This is the first study to provide evidence that therapy for GVHD should be changed on the basis of infiltrating cell type.

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.

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).

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).

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.

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

Fatty acid ethyl ester synthase inhibition ameliorates ethanol-induced Ca2+-dependent mitochondrial dysfunction and acute pancreatitis

PubMed Central

Huang, Wei; Booth, David M; Cane, Matthew C; Chvanov, Michael; Javed, Muhammad A; Elliott, Victoria L; Armstrong, Jane A; Dingsdale, Hayley; Cash, Nicole; Li, Yan; Greenhalf, William; Mukherjee, Rajarshi; Kaphalia, Bhupendra S; Jaffar, Mohammed; Petersen, Ole H; Tepikin, Alexei V; Sutton, Robert; Criddle, David N

2014-01-01

Objective Non-oxidative metabolism of ethanol (NOME) produces fatty acid ethyl esters (FAEEs) via carboxylester lipase (CEL) and other enzyme action implicated in mitochondrial injury and acute pancreatitis (AP). This study investigated the relative importance of oxidative and non-oxidative pathways in mitochondrial dysfunction, pancreatic damage and development of alcoholic AP, and whether deleterious effects of NOME are preventable. Design Intracellular calcium ([Ca2+]C), NAD(P)H, mitochondrial membrane potential and activation of apoptotic and necrotic cell death pathways were examined in isolated pancreatic acinar cells in response to ethanol and/or palmitoleic acid (POA) in the presence or absence of 4-methylpyrazole (4-MP) to inhibit oxidative metabolism. A novel in vivo model of alcoholic AP induced by intraperitoneal administration of ethanol and POA was developed to assess the effects of manipulating alcohol metabolism. Results Inhibition of OME with 4-MP converted predominantly transient [Ca2+]C rises induced by low ethanol/POA combination to sustained elevations, with concurrent mitochondrial depolarisation, fall of NAD(P)H and cellular necrosis in vitro. All effects were prevented by 3-benzyl-6-chloro-2-pyrone (3-BCP), a CEL inhibitor. 3-BCP also significantly inhibited rises of pancreatic FAEE in vivo and ameliorated acute pancreatic damage and inflammation induced by administration of ethanol and POA to mice. Conclusions A combination of low ethanol and fatty acid that did not exert deleterious effects per se became toxic when oxidative metabolism was inhibited. The in vitro and in vivo damage was markedly inhibited by blockade of CEL, indicating the potential for development of specific therapy for treatment of alcoholic AP via inhibition of FAEE generation. PMID:24162590

Disrupted sensory gating in pathological gambling.

PubMed

Stojanov, Wendy; Karayanidis, Frini; Johnston, Patrick; Bailey, Andrew; Carr, Vaughan; Schall, Ulrich

2003-08-15

Some neurochemical evidence as well as recent studies on molecular genetics suggest that pathologic gambling may be related to dysregulated dopamine neurotransmission. The current study examined sensory (motor) gating in pathologic gamblers as a putative measure of endogenous brain dopamine activity with prepulse inhibition of the acoustic startle eye-blink response and the auditory P300 event-related potential. Seventeen pathologic gamblers and 21 age- and gender-matched healthy control subjects were assessed. Both prepulse inhibition measures were recorded under passive listening and two-tone prepulse discrimination conditions. Compared to the control group, pathologic gamblers exhibited disrupted sensory (motor) gating on all measures of prepulse inhibition. Sensory motor gating deficits of eye-blink responses were most profound at 120-millisecond prepulse lead intervals in the passive listening task and at 240-millisecond prepulse lead intervals in the two-tone prepulse discrimination task. Sensory gating of P300 was also impaired in pathologic gamblers, particularly at 500-millisecond lead intervals, when performing the discrimination task on the prepulse. In the context of preclinical studies on the disruptive effects of dopamine agonists on prepulse inhibition, our findings suggest increased endogenous brain dopamine activity in pathologic gambling in line with previous neurobiological findings.

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

PubMed Central

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

2011-01-01

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

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

Lactobacillus johnsonii HY7042 ameliorates Gardnerella vaginalis-induced vaginosis by killing Gardnerella vaginalis and inhibiting NF-κB activation.

PubMed

Joo, Hyun-Min; Hyun, Yang-Jin; Myoung, Kil-Sun; Ahn, Young-Tae; Lee, Jung-Hee; Huh, Chul-Sung; Han, Myung Joo; Kim, Dong-Hyun

2011-11-01

Hydrogen peroxide-producing lactic acid bacteria (LAB) were isolated from women's vaginas and their anti-inflammatory effects against Gardnerella vaginalis-induced vaginosis were examined in β-estradiol-immunosuppressed mice. Oral and intravaginal treatment with five LABs significantly decreased viable G. vaginalis numbers in vaginal cavities and myeloperoxidase activity in mouse vaginal tissues. Of the LABs examined, Lactobacillus johnsonii HY7042 (LJ) most potently inhibited G. vaginalis-induced vaginosis. This LAB also inhibited the expressions of IL-1β, IL-6, TNF-α, COX-2, and iNOS, and the activation of NF-κB in vaginal tissues, but increased IL-10 expression. Orally administered LJ (0.2×10(8) CFU/mouse) also inhibited the expression of TNF-α by 91.7% in β-estradiol-immunosuppressed mice intraperitoneally injected with LPS. However, it increased IL-10 expression by 63.3% in these mice. Furthermore, LJ inhibited the expressions of the pro-inflammatory cytokines, TNF-α and IL-1β, and the activation of NF-κB in lipopolysaccharide-stimulated peritoneal macrophages. LJ also killed G. vaginalis attached with and without HeLa cells. These findings suggest that LJ inhibits bacterial vaginosis by inhibiting the expressions of COX-2, iNOS, IL-1β, and TNF-α by regulating NF-κB activation and by killing G. vaginalis, and that LJ could ameliorate bacterial vaginosis. Copyright © 2011 Elsevier B.V. All rights reserved.

Ghrelin ameliorates acute lung injury induced by oleic acid via inhibition of endoplasmic reticulum stress.

PubMed

Tian, Xiuli; Liu, Zhijun; Yu, Ting; Yang, Haitao; Feng, Linlin

2018-03-01

Acute lung injury (ALI) is associated with excessive mortality and lacks appropriate therapy. Ghrelin is a novel peptide that protects the lung against ALI. This study aimed to investigate whether endoplasmic reticulum stress (ERS) mediates the protective effect of ghrelin on ALI. We used a rat oleic acid (OA)-induced ALI model. Pulmonary impairment was detected by hematoxylin and eosin (HE) staining, lung mechanics, wet/dry weight ratio, and arterial blood gas analysis. Plasma and lung content of ghrelin was examined by ELISA, and mRNA expression was measured by quantitative real-time PCR. Protein levels were detected by western blot. Rats with OA treatment showed significant pulmonary injury, edema, inflammatory cellular infiltration, cytokine release, hypoxia and CO 2 retention as compared with controls. Plasma and pulmonary content of ghrelin was reduced in rats with ALI, and mRNA expression was downregulated. Ghrelin (10nmol/kg) treatment ameliorated the above symptoms, but treatment with the ghrelin antagonists D-Lys 3 GHRP-6 (1μmol/kg) and JMV 2959 (6mg/kg) exacerbated the symptoms. ERS induced by OA was prevented by ghrelin and augmented by ghrelin antagonist treatment. The ERS inducer, tunicamycin (Tm) prevented the ameliorative effect of ghrelin on ALI. The decreased ratio of p-Akt and Akt induced by OA was improved by ghrelin treatment, and was further exacerbated by ghrelin antagonists. Ghrelin protects against ALI by inhibiting ERS. These results provide a new target for prevention and therapy of ALI. Copyright © 2017 Elsevier Inc. All rights reserved.

Amelioration of bleomycin-induced pulmonary fibrosis by chlorogenic acid through endoplasmic reticulum stress inhibition.

PubMed

Wang, Yi-Chun; Dong, Jing; Nie, Jing; Zhu, Ji-Xiang; Wang, Hui; Chen, Qiong; Chen, Jun-Yi; Xia, Jia-Mei; Shuai, Wei

2017-09-01

To investigate the inhibitory effects of chlorogenic acid on pulmonary fibrosis and the internal mechanisms in vivo and in vitro. 30 male BALB/C mice were randomized into 5 groups: control group, pulmonary fibrosis model group, low, middle and high dose of chlorogenic acid groups. Mice in pulmonary fibrosis model group were administered 5.0 mg/kg bleomycin with intracheal instillation and mice in 3 chlorogenic acid groups were treated with chlorogenic acid every day for 28 days after bleomycin administration. Lung tissue histology was observed using HE staining. Primary pulmonary fibroblasts were isolated and cultured. The expressions of fibrosis related factors (α-SMA and collagen I), as well as ER stress markers (CHOP and GRP78) were determined by both real-time PCR assay and Western blotting, while the expressions of other ER stress signaling pathway factors PERK, IRE-1, ATF-6 and protein levels of caspase-12, caspase-9, caspase-3, PARP were determined by Western blotting. RLE-6TN cell line induced by TGF-β1 was also used to verify the amelioration effects in vitro study. In both in vivo and in vitro studies, TUNEL staining was used to evaluate cell apoptosis. Expressions of collagen I, α-SMA, GRP78, and CHOP were significantly inhibited by chlorogenic acid in dose-dependent manner. Similarly, decreasing levels of cleaved caspase-12, caspase-9, caspase-3 and increasing level of uncleaved PARP were observed in chlorogenic acid groups compared with those in the fibrosis group both in vivo and in vitro. Chlorogenic acid could also significantly down-regulate the level of phosphorylation of PERK and cleaved ATF-6 in vivo study. Moreover, MTT assay demonstrated chlorogenic acid could enhance proliferation of RLE-6TN cells induced by TGFβ1 in vitro. And the apoptosis assays indicated that chlorogenic acid could significantly inhibit cell apoptosis both in vivo and in vitro studies. Chlorogenic acid could inhibit the pulmonary fibrosis through endoplasmic

Differential inhibition of N and P/Q Ca2+ currents by 5-HT1A and 5-HT1D receptors in spinal neurons of Xenopus larvae

PubMed Central

Sun, Qian-Quan; Dale, Nicholas

1998-01-01

In whole-cell patch clamp recordings made from non-sensory neurons acutely isolated from the spinal cord of Xenopus (stage 40–42) larvae, two forms of inhibition of the high voltage-activated (HVA) Ca2+ currents were produced by 5-HT. One was voltage dependent and associated with both slowing of the activation kinetics and shifting of the voltage dependence of the HVA currents. This inhibition was relieved by strong depolarizing prepulses. A second form of inhibition was neither associated with slowing of the activation kinetics nor relieved by depolarizing prepulses and was thus voltage independent. In all neurons examined, 5-HT (1 μM) reversibly reduced 34 ± 1.6 % (n = 102) of the HVA Ca2+ currents. In about 40 % of neurons, the inhibition was totally voltage independent. In another 5 %, the inhibition was totally voltage dependent. In the remaining neurons, inhibition was only partially (by around 40 %) relieved by a large depolarizing prepulse, suggesting that in these, the inhibition consisted of both voltage-dependent and -independent components. By using selective channel blockers, we found that 5-HT acted on both N- and P/Q-type channels. However, whereas the inhibition of P/Q-type currents was only voltage independent, the inhibition of N-type currents had both voltage-dependent and -independent components. The effects of 5-HT on HVA Ca2+ currents were mediated by 5-HT1A and 5-HT1D receptors. The 5-HT1A receptors not only preferentially caused voltage-independent inhibition, but did so by acting mainly on the ω-agatoxin-IVA-sensitive Ca2+ channels. In contrast, the 5-HT1D receptor produced both voltage-dependent and -independent inhibition and was preferentially coupled to ω-conotoxin-GVIA sensitive channels. This complexity of modulation may allow fine tuning of transmitter release and calcium signalling in the spinal circuitry of Xenopus larvae. PMID:9625870

Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents

PubMed Central

Asshoff, Malte; Petzer, Verena; Warr, Matthew R.; Haschka, David; Tymoszuk, Piotr; Demetz, Egon; Seifert, Markus; Posch, Wilfried; Nairz, Manfred; Maciejewski, Pat; Fowles, Peter; Burns, Christopher J.; Smith, Gregg; Wagner, Kay-Uwe; Weiss, Guenter; Whitney, J. Andrew

2017-01-01

Patients with myelofibrosis (MF) often develop anemia and frequently become dependent on red blood cell transfusions. Results from a phase 2 study for the treatment of MF with the Janus kinase 1/2 (JAK1/2) inhibitor momelotinib (MMB) demonstrated that MMB treatment ameliorated anemia, which was unexpected for a JAK1/2 inhibitor, because erythropoietin-mediated JAK2 signaling is essential for erythropoiesis. Using a rat model of anemia of chronic disease, we demonstrated that MMB treatment can normalize hemoglobin and red blood cell numbers. We found that this positive effect is driven by direct inhibition of the bone morphogenic protein receptor kinase activin A receptor, type I (ACVR1), and the subsequent reduction of hepatocyte hepcidin production. Of note, ruxolitinib, a JAK1/2 inhibitor approved for the treatment of MF, had no inhibitory activity on this pathway. Further, we demonstrated the effect of MMB is not mediated by direct inhibition of JAK2-mediated ferroportin (FPN1) degradation, because neither MMB treatment nor myeloid-specific deletion of JAK2 affected FPN1 expression. Our data support the hypothesis that the improvement of inflammatory anemia by MMB results from inhibition of ACVR1-mediated hepcidin expression in the liver, which leads to increased mobilization of sequestered iron from cellular stores and subsequent stimulation of erythropoiesis. PMID:28188131

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

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

Xing, Xiaomang; Li, Danyang; Chen, Dilong

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,more » 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

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.

Sodium alginate ameliorates indomethacin-induced gastrointestinal mucosal injury via inhibiting translocation in rats

PubMed Central

Yamamoto, Atsuki; Itoh, Tomokazu; Nasu, Reishi; Nishida, Ryuichi

2014-01-01

AIM: To investigate the effects of sodium alginate (AL-Na) on indomethacin-induced small intestinal lesions in rats. METHODS: Gastric injury was assessed by measuring ulcerated legions 4 h after indomethacin (25 mg/kg) administration. Small intestinal injury was assessed by measuring ulcerated legions 24 h after indomethacin (10 mg/kg) administration. AL-Na and rebamipide were orally administered. Myeloperoxidase activity in the stomach and intestine were measured. Microvascular permeability, superoxide dismutase content, glutathione peroxidase activity, catalase activity, red blood cell count, white blood cell count, mucin content and enterobacterial count in the small intestine were measured. RESULTS: AL-Na significantly reduced indomethacin-induced ulcer size and myeloperoxidase activity in the stomach and small intestine. AL-Na prevented increases in microvascular permeability, superoxide dismutase content, glutathione peroxidase activity and catalase activity in small intestinal injury induced by indomethacin. AL-Na also prevented decreases in red blood cells and white blood cells in small intestinal injury induced by indomethacin. Moreover, AL-Na suppressed mucin depletion by indomethacin and inhibited infiltration of enterobacteria into the small intestine. CONCLUSION: These results indicate that AL-Na ameliorates non-steroidal anti-inflammatory drug-induced small intestinal enteritis via bacterial translocation. PMID:24627600

Rapamycin ameliorates neuropathic pain by activating autophagy and inhibiting interleukin-1β in the rat spinal cord.

PubMed

Feng, Tao; Yin, Qin; Weng, Ze-lin; Zhang, Jian-cheng; Wang, Kun-feng; Yuan, Shi-ying; Cheng, Wei

2014-12-01

Autophagy acts as an important homoeostatic mechanism by degradation of cytosolic constituents and plays roles in many physiological processes. Recent studies demonstrated that autophagy can also regulate the production and secretion of the proinflammatory cytokine interleukin-1β (IL-1β), which plays a critical role in the development and maintenance of neuropathic pain. In the present study, the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were significantly decreased after spinal nerve ligation (SNL), and the changes were accompanied by inhibited autophagy in the spinal microglia and increased mRNA and protein levels of IL-1β in the ipsilateral spinal cord. We then investigated the antinociceptive effect of rapamycin, a widely used autopahgy inducer, on SNL-induced neuropathic pain in rats and found that treatment with intrathecal rapamycin significantly attenuated the mechanical allodynia and thermal hyperalgesia. Moreover, rapamycin significantly enhanced autophagy in the spinal microglia, whereas it reduced the mRNA and protein levels of IL-1β in the ipsilateral spinal cord. Our results showed that rapamycin could ameliorate neuropathic pain by activating autophagy and inhibiting IL-1β in the spinal cord.

Hydrogen sulfide ameliorates aging-associated changes in the kidney.

PubMed

Lee, Hak Joo; Feliers, Denis; Barnes, Jeffrey L; Oh, Sae; Choudhury, Goutam Ghosh; Diaz, Vivian; Galvan, Veronica; Strong, Randy; Nelson, James; Salmon, Adam; Kevil, Christopher G; Kasinath, Balakuntalam S

2018-04-01

Aging is associated with replacement of normal kidney parenchyma by fibrosis. Because hydrogen sulfide (H 2 S) ameliorates kidney fibrosis in disease models, we examined its status in the aging kidney. In the first study, we examined kidney cortical H 2 S metabolism and signaling pathways related to synthesis of proteins including matrix proteins in young and old male C57BL/6 mice. In old mice, increase in renal cortical content of matrix protein involved in fibrosis was associated with decreased H 2 S generation and AMPK activity, and activation of insulin receptor (IR)/IRS-2-Akt-mTORC1-mRNA translation signaling axis that can lead to increase in protein synthesis. In the second study, we randomized 18-19 month-old male C57BL/6 mice to receive 30 μmol/L sodium hydrosulfide (NaHS) in drinking water vs. water alone (control) for 5 months. Administration of NaHS increased plasma free sulfide levels. NaHS inhibited the increase in kidney cortical content of matrix proteins involved in fibrosis and ameliorated glomerulosclerosis. NaHS restored AMPK activity and inhibited activation of IR/IRS-2-Akt-mTORC1-mRNA translation axis. NaHS inhibited age-related increase in kidney cortical content of p21, IL-1β, and IL-6, components of the senescence-associated secretory phenotype. NaHS abolished increase in urinary albumin excretion seen in control mice and reduced serum cystatin C levels suggesting improved glomerular clearance function. We conclude that aging-induced changes in the kidney are associated with H 2 S deficiency. Administration of H 2 S ameliorates aging-induced kidney changes probably by inhibiting signaling pathways leading to matrix protein synthesis.

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.

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

PubMed Central

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

2013-01-01

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

The roles of 5-HT1A and 5-HT2 receptors in the effects of 5-MeO-DMT on locomotor activity and prepulse inhibition in rats.

PubMed

Krebs-Thomson, Kirsten; Ruiz, Erbert M; Masten, Virginia; Buell, Mahalah; Geyer, Mark A

2006-12-01

The hallucinogen 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is structurally similar to other indoleamine hallucinogens such as LSD. The present study examined the effects of 5-MeO-DMT in rats using the Behavioral Pattern Monitor (BPM), which enables analyses of patterns of locomotor activity and exploration, and the prepulse inhibition of startle (PPI) paradigm. A series of interaction studies using the serotonin (5-HT)(1A) antagonist WAY-100635 (1.0 mg/kg), the 5-HT(2A) antagonist M100907 (1.0 mg/kg), and the 5-HT(2C) antagonist SER-082 (0.5 mg/kg) were performed to assess the respective contributions of these receptors to the behavioral effects of 5-MeO-DMT (0.01, 0.1, and 1.0 mg/kg) in the BPM and PPI paradigms. 5-MeO-DMT decreased locomotor activity, investigatory behavior, the time spent in the center of the BPM chamber, and disrupted PPI. All of these effects were antagonized by WAY-100635 pretreatment. M100907 pretreatment failed to attenuate any of these effects, while SER-082 pretreatment only antagonized the PPI disruption produced by 5-MeO-DMT. While the prevailing view was that the activation of 5-HT(2) receptors is solely responsible for hallucinogenic drug effects, these results support a role for 5-HT(1A) receptors in the effects of the indoleamine hallucinogen 5-MeO-DMT on locomotor activity and PPI in rats.

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

PubMed

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

2016-07-01

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

The amelioration of phagocytic ability in microglial cells by curcumin through the inhibition of EMF-induced pro-inflammatory responses

PubMed Central

2014-01-01

. Western blot analysis revealed that curcumin and naloxone restored the expression of MFG-E8 but had no effect on TLR4 and cytosolic STAT3. Moreover, curcumin significantly reduced the expression of NF-κB p65 in nuclei and phospho-STAT3 (p-STAT3) in cytosols and nuclei. Conclusions This study indicates that curcumin ameliorates the depressed MFG-E8 expression and the attenuated phagocytic ability of EMF-exposed N9 cells, which is attributable to the inhibition of the pro-inflammatory response through the NF-κB and STAT3 pathways. PMID:24645646

Celecoxib and octreotide synergistically ameliorate portal hypertension via inhibition of angiogenesis in cirrhotic rats.

PubMed

Gao, Jin-Hang; Wen, Shi-Lei; Feng, Shi; Yang, Wen-Juan; Lu, Yao-Yao; Tong, Huan; Liu, Rui; Tang, Shi-Hang; Huang, Zhi-Yin; Tang, Ying-Mei; Yang, Jin-Hui; Xie, Hui-Qi; Tang, Cheng-Wei

2016-10-01

Abnormal angiogenesis is critical for portal hypertension in cirrhosis. Except for etiological treatment, no efficient medication or regime has been explored to treat the early stage of cirrhosis when angiogenesis is initiated or overwhelming. In this study, we explored an anti-angiogenesis effort through non-cytotoxic drugs octreotide and celecoxib to treat early stage of cirrhotic portal hypertension in an animal model. Peritoneal injection of thioacetamide (TAA) was employed to induce liver cirrhosis in rats. A combination treatment of celecoxib and octreotide was found to relieve liver fibrosis, portal venous pressure, micro-hepatic arterioportal fistulas, intrahepatic and splanchnic angiogenesis. Celecoxib and octreotide exerted their anti-angiogenesis effect via an axis of cyclooxygenase-2/prostaglandin E2/EP-2/somatostatin receptor-2, which consequently down-regulated phosphorylation of extracellular signal-regulated kinase (p-ERK)-hypoxia-inducible factor-1α (HIF-1α)-vascular endothelial growth factor (VEGF) integrated signaling pathways. In conclusions, combination of celecoxib and octreotide synergistically ameliorated liver fibrosis and portal hypertension of the cirrhotic rats induced by TAA via the inhibition of intrahepatic and extrahepatic angiogenesis. The potential mechanisms behind the regimen may due to the inactivation of p-ERK-HIF-1α-VEGF signaling pathway.

An investigation into "two hit" effects of BDNF deficiency and young-adult cannabinoid receptor stimulation on prepulse inhibition regulation and memory in mice.

PubMed

Klug, Maren; van den Buuse, Maarten

2013-01-01

Reduced brain-derived neurotrophic factor (BDNF) signaling has been shown in the frontal cortex and hippocampus in schizophrenia. The aim of the present study was to investigate whether a BDNF deficit would modulate effects of chronic cannabis intake, a well-described risk factor for schizophrenia development. BDNF heterozygous mice (HET) and wild-type controls were chronically treated during weeks 6, 7, and 8 of life with the cannabinoid receptor agonist, CP55,940 (CP). After a 2-week delay, there were no CP-induced deficits in any of the groups in short-term spatial memory in a Y-maze task or novel object recognition memory. Baseline prepulse inhibition (PPI) was lower but average startle was increased in BDNF HET compared to wild-type controls. Acute CP administration before the PPI session caused a marked increase in PPI in male HET mice pre-treated with CP but not in any of the other male groups. In females, there were small increases of PPI in all groups upon acute CP administration. Acute CP administration furthermore reduced startle and this effect was greater in HET mice irrespective of chronic CP pre-treatment. Analysis of the levels of [(3)H]CP55,940 binding by autoradiography revealed a significant increase in the nucleus accumbens of male BDNF HET mice previously treated with CP but not in any of the other groups or in the caudate nucleus. These results show that BDNF deficiency and chronic young-adult cannabinoid receptor stimulation do not interact in this model on learning and memory later in life. In contrast, male "two hit" mice, but not females, were hypersensitive to the effect of acute CP on sensorimotor gating. These effects may be related to a selective increase of [(3)H]CP55,940 binding in the nucleus accumbens, reflecting up-regulation of CB1 receptor density in this region. These data could be of relevance to our understanding of differential "two hit" neurodevelopmental mechanisms in schizophrenia.

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

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

Cheng, Jian; Zhang, Lin; Dai, Weiqi

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 alsomore » 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.« less

Fluoxetine ameliorates cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling.

PubMed

Miyamoto, Kentaro; Ohkawara, Bisei; Ito, Mikako; Masuda, Akio; Hirakawa, Akihiro; Sakai, Tadahiro; Hiraiwa, Hideki; Hamada, Takashi; Ishiguro, Naoki; Ohno, Kinji

2017-01-01

Abnormal activation of the Wnt/β-catenin signaling is implicated in the osteoarthritis (OA) pathology. We searched for a pre-approved drug that suppresses abnormally activated Wnt/β-catenin signaling and has a potency to reduce joint pathology in OA. We introduced the TOPFlash reporter plasmid into HCS-2/8 human chondrosarcoma cells to estimate the Wnt/β-catenin activity in the presence of 10 μM each compound in a panel of pre-approved drugs. We found that fluoxetine, an antidepressant in the class of selective serotonin reuptake inhibitors (SSRI), down-regulated Wnt/β-catenin signaling in human chondrosarcoma cells. Fluoxetine inhibited both Wnt3A- and LiCl-induced loss of proteoglycans in chondrogenically differentiated ATDC5 cells. Fluoxetine increased expression of Sox9 (the chondrogenic master regulator), and decreased expressions of Axin2 (a marker for Wnt/β-catenin signaling) and Mmp13 (matrix metalloproteinase 13). Fluoxetine suppressed a LiCl-induced increase of total β-catenin and a LiCl-induced decrease of phosphorylated β-catenin in a dose-dependent manner. An in vitro protein-binding assay showed that fluoxetine enhanced binding of β-catenin with Axin1, which is a scaffold protein forming the degradation complex for β-catenin. Fluoxetine suppressed LiCl-induced β-catenin accumulation in human OA chondrocytes. Intraarticular injection of fluoxetine in a rat OA model ameliorated OA progression and suppressed β-catenin accumulation.

Fluoxetine ameliorates cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling

PubMed Central

Miyamoto, Kentaro; Ito, Mikako; Masuda, Akio; Hirakawa, Akihiro; Sakai, Tadahiro; Hiraiwa, Hideki; Hamada, Takashi; Ishiguro, Naoki; Ohno, Kinji

2017-01-01

Abnormal activation of the Wnt/β-catenin signaling is implicated in the osteoarthritis (OA) pathology. We searched for a pre-approved drug that suppresses abnormally activated Wnt/β-catenin signaling and has a potency to reduce joint pathology in OA. We introduced the TOPFlash reporter plasmid into HCS-2/8 human chondrosarcoma cells to estimate the Wnt/β-catenin activity in the presence of 10 μM each compound in a panel of pre-approved drugs. We found that fluoxetine, an antidepressant in the class of selective serotonin reuptake inhibitors (SSRI), down-regulated Wnt/β-catenin signaling in human chondrosarcoma cells. Fluoxetine inhibited both Wnt3A- and LiCl-induced loss of proteoglycans in chondrogenically differentiated ATDC5 cells. Fluoxetine increased expression of Sox9 (the chondrogenic master regulator), and decreased expressions of Axin2 (a marker for Wnt/β-catenin signaling) and Mmp13 (matrix metalloproteinase 13). Fluoxetine suppressed a LiCl-induced increase of total β-catenin and a LiCl-induced decrease of phosphorylated β-catenin in a dose-dependent manner. An in vitro protein-binding assay showed that fluoxetine enhanced binding of β-catenin with Axin1, which is a scaffold protein forming the degradation complex for β-catenin. Fluoxetine suppressed LiCl-induced β-catenin accumulation in human OA chondrocytes. Intraarticular injection of fluoxetine in a rat OA model ameliorated OA progression and suppressed β-catenin accumulation. PMID:28926590

Sub-threshold depolarizing pre-pulses can enhance the efficiency of biphasic stimuli in transcutaneous neuromuscular electrical stimulation.

PubMed

Vargas Luna, Jose Luis; Mayr, Winfried; Cortés-Ramirez, Jorge-Armando

2018-06-09

There is multiple evidence in the literature that a sub-threshold pre-pulse, delivered immediately prior to an electrical stimulation pulse, can alter the activation threshold of nerve fibers and motor unit recruitment characteristics. So far, previously published works combined monophasic stimuli with sub-threshold depolarizing pre-pulses (DPPs) with inconsistent findings-in some studies, the DPPs decreased the activation threshold, while in others it was increased. This work aimed to evaluate the effect of DPPs during biphasic transcutaneous electrical stimulation and to study the possible mechanism underlying those differences. Sub-threshold DPPs between 0.5 and 15 ms immediately followed by biphasic or monophasic pulses were administered to the tibial nerve; the electrophysiological muscular responses (motor-wave, M-wave) were monitored via electromyogram (EMG) recording from the soleus muscle. The data show that, under the specific studied conditions, DPPs tend to lower the threshold for nerve fiber activation rather than elevating it. DPPs with the same polarity as the leading phase of biphasic stimuli are more effective to increase the sensitivity. This work assesses for the first time the effect of DPPs on biphasic pulses, which are required to achieve charge-balanced stimulation, and it provides guidance on the effect of polarity and intensity to take full advantage of this feature. Graphical abstract In this work, the effect of sub-threshold depolarizing pre-pulses (DPP) is investigated in a setup with transcutaneous electrical stimulation. We found that, within the tested 0-15 ms DPP duration range, the DPPs administered immediately before biphasic pulses proportionally increase the nerve excitability as visible in the M-waves recorded from the soleus muscle. Interestingly, these findings oppose published results, where DPPs, administered immediately before monophasic stimuli via implanted electrodes, led to decrease of nerve excitability.

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

PubMed

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

2014-01-01

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

Hydrogen Sulfide Ameliorates Homocysteine-Induced Cognitive Dysfunction by Inhibition of Reactive Aldehydes Involving Upregulation of ALDH2.

PubMed

Li, Min; Zhang, Ping; Wei, Hai-Jun; Li, Man-Hong; Zou, Wei; Li, Xiang; Gu, Hong-Feng; Tang, Xiao-Qing

2017-04-01

Homocysteine, a risk factor for Alzheimer's disease, induces cognitive dysfunction. Reactive aldehydes play an important role in cognitive dysfunction. Aldehyde-dehydrogenase 2 detoxifies reactive aldehydes. Hydrogen sulfide, a novel neuromodulator, has neuroprotective effects and regulates learning and memory. Our previous work confirmed that the disturbance of hydrogen sulfide synthesis is invovled in homocysteine-induced defects in learning and memory. Therefore, the present work was to explore whether hydrogen sulfide ameliorates homocysteine-generated cognitive dysfunction and to investigate whether its underlying mechanism is related to attenuating accumulation of reactive aldehydes by upregulation of aldehyde-dehydrogenase 2. The cognitive function of rats was assessed by the Morris water maze test and the novel object recognition test. The levels of malondialdehyde, 4-hydroxynonenal, and glutathione as well as the activity of aldehyde-dehydrogenase 2 were determined by enzyme linked immunosorbent assay; the expression of aldehyde-dehydrogenase 2 was detected by western blot. The behavior experiments, Morris water maze test and novel objects recognition test, showed that homocysteine induced deficiency in learning and memory in rats, and this deficiency was reversed by treatment of NaHS (a donor of hydrogen sulfide). We demonstrated that NaHS inhibited homocysteine-induced increases in generations of MDA and 4-HNE in the hippocampus of rats and that hydrogen sulfide reversed homocysteine-induced decreases in the level of glutathione as well as the activity and expression of aldehyde-dehydrogenase 2 in the hippocampus of rats. Hydrogen sulfide ameliorates homocysteine-induced impairment in cognitive function by decreasing accumulation of reactive aldehydes as a result of upregulations of glutathione and aldehyde-dehydrogenase 2. © The Author 2016. Published by Oxford University Press on behalf of CINP.

Hydrogen Sulfide Ameliorates Homocysteine-Induced Cognitive Dysfunction by Inhibition of Reactive Aldehydes Involving Upregulation of ALDH2

PubMed Central

Li, Min; Zhang, Ping; Wei, Hai-jun; Li, Man-Hong; Li, Xiang; Gu, Hong-Feng

2017-01-01

Abstract Background: Homocysteine, a risk factor for Alzheimer’s disease, induces cognitive dysfunction. Reactive aldehydes play an important role in cognitive dysfunction. Aldehyde-dehydrogenase 2 detoxifies reactive aldehydes. Hydrogen sulfide, a novel neuromodulator, has neuroprotective effects and regulates learning and memory. Our previous work confirmed that the disturbance of hydrogen sulfide synthesis is invovled in homocysteine-induced defects in learning and memory. Therefore, the present work was to explore whether hydrogen sulfide ameliorates homocysteine-generated cognitive dysfunction and to investigate whether its underlying mechanism is related to attenuating accumulation of reactive aldehydes by upregulation of aldehyde-dehydrogenase 2. Methods: The cognitive function of rats was assessed by the Morris water maze test and the novel object recognition test. The levels of malondialdehyde, 4-hydroxynonenal, and glutathione as well as the activity of aldehyde-dehydrogenase 2 were determined by enzyme linked immunosorbent assay; the expression of aldehyde-dehydrogenase 2 was detected by western blot. Results: The behavior experiments, Morris water maze test and novel objects recognition test, showed that homocysteine induced deficiency in learning and memory in rats, and this deficiency was reversed by treatment of NaHS (a donor of hydrogen sulfide). We demonstrated that NaHS inhibited homocysteine-induced increases in generations of MDA and 4-HNE in the hippocampus of rats and that hydrogen sulfide reversed homocysteine-induced decreases in the level of glutathione as well as the activity and expression of aldehyde-dehydrogenase 2 in the hippocampus of rats. Conclusion: Hydrogen sulfide ameliorates homocysteine-induced impairment in cognitive function by decreasing accumulation of reactive aldehydes as a result of upregulations of glutathione and aldehyde-dehydrogenase 2. PMID:27988490

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

NASA Astrophysics Data System (ADS)

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

2009-01-01

The Sphinx machine[1] is a 6 MA, 1 μS 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[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 η 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.

An investigation into “two hit” effects of BDNF deficiency and young-adult cannabinoid receptor stimulation on prepulse inhibition regulation and memory in mice

PubMed Central

Klug, Maren; van den Buuse, Maarten

2013-01-01

Reduced brain-derived neurotrophic factor (BDNF) signaling has been shown in the frontal cortex and hippocampus in schizophrenia. The aim of the present study was to investigate whether a BDNF deficit would modulate effects of chronic cannabis intake, a well-described risk factor for schizophrenia development. BDNF heterozygous mice (HET) and wild-type controls were chronically treated during weeks 6, 7, and 8 of life with the cannabinoid receptor agonist, CP55,940 (CP). After a 2-week delay, there were no CP-induced deficits in any of the groups in short-term spatial memory in a Y-maze task or novel object recognition memory. Baseline prepulse inhibition (PPI) was lower but average startle was increased in BDNF HET compared to wild-type controls. Acute CP administration before the PPI session caused a marked increase in PPI in male HET mice pre-treated with CP but not in any of the other male groups. In females, there were small increases of PPI in all groups upon acute CP administration. Acute CP administration furthermore reduced startle and this effect was greater in HET mice irrespective of chronic CP pre-treatment. Analysis of the levels of [3H]CP55,940 binding by autoradiography revealed a significant increase in the nucleus accumbens of male BDNF HET mice previously treated with CP but not in any of the other groups or in the caudate nucleus. These results show that BDNF deficiency and chronic young-adult cannabinoid receptor stimulation do not interact in this model on learning and memory later in life. In contrast, male “two hit” mice, but not females, were hypersensitive to the effect of acute CP on sensorimotor gating. These effects may be related to a selective increase of [3H]CP55,940 binding in the nucleus accumbens, reflecting up-regulation of CB1 receptor density in this region. These data could be of relevance to our understanding of differential “two hit” neurodevelopmental mechanisms in schizophrenia. PMID:24155701

Inhibition of 12/15-LO ameliorates CVB3-induced myocarditis by activating Nrf2.

PubMed

Ai, Feng; Zheng, Jiayong; Zhang, Yanwei; Fan, Taibing

2017-06-25

Cardiac 12/15-lipoxygenase (12/15-LO) was reported to be markedly up-regulated and involved in the development of heart failure. Nuclear factor E2-related factor 2 (Nrf2) plays anti-inflammatory and anti-oxidation roles in response to oxidative stress. However, the role of 12/15-LO in viral myocarditis (VMC) and its underlying molecular mechanism have not yet been elucidated. Here, we demonstrated that 12/15-LO was up-regulated and Nrf2 was down-regulated in coxsackievirus B3 (CVB3)-infected mice and cardiac myocytes. Baicalein, the specific inhibitor of 12/15-LO, was employed to investigate the role of 12/15-LO and its underlying mechanism in VMC. We found that baicalein treatment alleviated CVB3-induced VMC mouse models, as demonstrated by less inflammatory lesions in the heart tissues and less CK-MB level. Moreover, baicalein treatment attenuated CVB3-induced inflammatory cytokine production and oxidative stress. Mechanistic analysis suggested that baicalein treatment relieved CVB3-induced reduction of Nrf2 and heme oxygenase-1 (HO-1) expressions. Taken together, our study indicated that inhibition of 12/15-LO ameliorates VMC by activating Nrf2, providing a new therapeutic strategy for the therapy of VMC. Copyright © 2017 Elsevier B.V. All rights reserved.

Dependence of the Startle Response on Temporal and Spectral Characteristics of Acoustic Modulatory Influences in Rats and Gerbils

PubMed Central

Steube, Natalie; Nowotny, Manuela; Pilz, Peter K. D.; Gaese, Bernhard H.

2016-01-01

The acoustic startle response (ASR) and its modulation by non-startling prepulses, presented shortly before the startle-eliciting stimulus, is a broadly applied test paradigm to determine changes in neural processing related to auditory or psychiatric disorders. Modulation by a gap in background noise as a prepulse is especially used for tinnitus assessment. However, the timing and frequency-related aspects of prepulses are not fully understood. The present study aims to investigate temporal and spectral characteristics of acoustic stimuli that modulate the ASR in rats and gerbils. For noise-burst prepulses, inhibition was frequency-independent in gerbils in the test range between 4 and 18 kHz. Prepulse inhibition (PPI) by noise-bursts in rats was constant in a comparable range (8–22 kHz), but lower outside this range. Purely temporal aspects of prepulse–startle-interactions were investigated for gap-prepulses focusing mainly on gap duration. While very short gaps had no (rats) or slightly facilitatory (gerbils) influence on the ASR, longer gaps always had a strong inhibitory effect. Inhibition increased with durations up to 75 ms and remained at a high level of inhibition for durations up to 1000 ms for both, rats and gerbils. Determining spectral influences on gap-prepulse inhibition (gap-PPI) revealed that gerbils were unaffected in the limited frequency range tested (4–18 kHz). The more detailed analysis in rats revealed a variety of frequency-dependent effects. Gaps in pure-tone background elicited constant and high inhibition (around 75%) over a broad frequency range (4–32 kHz). For gaps in noise-bands, on the other hand, a clear frequency-dependency was found: inhibition was around 50% at lower frequencies (6–14 kHz) and around 70% at high frequencies (16–20 kHz). This pattern of frequency-dependency in rats was specifically resulting from the inhibitory effect by the gaps, as revealed by detailed analysis of the underlying startle amplitudes. An

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. Copyright © 2016 Elsevier Inc. All rights reserved.

Interaction of reelin and stress on immobility in the forced swim test but not dopamine-mediated locomotor hyperactivity or prepulse inhibition disruption: Relevance to psychotic and mood disorders.

PubMed

Notaras, Michael J; Vivian, Billie; Wilson, Carey; van den Buuse, Maarten

2017-07-13

Psychotic disorders, such as schizophrenia, as well as some mood disorders, such as bipolar disorder, have been suggested to share common biological risk factors. One such factor is reelin, a large extracellular matrix glycoprotein that regulates neuronal migration during development as well as numerous activity-dependent processes in the adult brain. The current study sought to evaluate whether a history of stress exposure interacts with endogenous reelin levels to modify behavioural endophenotypes of relevance to psychotic and mood disorders. Heterozygous Reeler Mice (HRM) and wildtype (WT) controls were treated with 50mg/L of corticosterone (CORT) in their drinking water from 6 to 9weeks of age, before undergoing behavioural testing in adulthood. We assessed methamphetamine-induced locomotor hyperactivity, prepulse inhibition (PPI) of acoustic startle, short-term spatial memory in the Y-maze, and depression-like behaviour in the Forced-Swim Test (FST). HRM genotype or CORT treatment did not affect methamphetamine-induced locomotor hyperactivity, a model of psychosis-like behaviour. At baseline, HRM showed decreased PPI at the commonly used 100msec interstimulus interval (ISI), but not at the 30msec ISI or following challenge with apomorphine. A history of CORT exposure potentiated immobility in the FST amongst HRM, but not WT mice. In the Y-maze, chronic CORT treatment decreased novel arm preference amongst HRM, reflecting reduced short-term spatial memory. These data confirm a significant role of endogenous reelin levels on stress-related behaviour, supporting a possible role in both bipolar disorder and schizophrenia. However, an interaction of reelin deficiency with dopaminergic regulation of psychosis-like behaviour remains unclear. Copyright © 2017 Elsevier B.V. All rights reserved.

Piper nigrum extract ameliorated allergic inflammation through inhibiting Th2/Th17 responses and mast cells activation.

PubMed

Bui, Thi Tho; Piao, Chun Hua; Song, Chang Ho; Shin, Hee Soon; Shon, Dong-Hwa; Chai, Ok Hee

2017-12-01

Piper nigrum (Piperaceae) is commonly used as a spice and traditional medicine in many countries. P. nigrum has been reported to have anti-oxidant, anti-bacterial, anti-tumor, anti-mutagenic, anti-diabetic, and anti-inflammatory properties. However, the effect of P. nigrum on allergic asthma has not been known. This study investigated the effect of P. nigrum ethanol extracts (PNE) on airway inflammation in asthmatic mice model. In the ovalbumin (OVA)-induced allergic asthma model, we analysed the number of inflammatory cells and cytokines production in bronchoalveolar lavage fluid (BALF) and lung tissue; histological structure; as well as the total immunoglobulin (Ig)E, anti-OVA IgE, anti-OVA IgG 1 and histamine levels in serum. The oral administration (200 mg/kg) of PNE reduced the accumulation of inflammatory cells (eosinophils, neutrophils in BALF and mast cells in lung tissue); regulated the balance of the cytokines production of Th1, Th2, Th17 and Treg cells, specifically, inhibited the expressions of GATA3, IL-4, IL-6, IL-1β, RORγt, IL-17A, TNF-α and increased the secretions of IL-10, INF-γ in BALF and lung homogenate. Moreover, PNE suppressed the levels of total IgE, anti-OVA IgE, anti-OVA IgG 1 and histamine release in serum. The histological analysis showed that the fibrosis and infiltration of inflammatory cells were also ameliorated in PNE treated mice. On the other hand, PNE inhibited the allergic responses via inactivation of rat peritoneal mast cells degranulation. These results suggest that PNE has therapeutic potential for treating allergic asthma through inhibiting Th2/Th17 responses and mast cells activation. Copyright © 2017 Elsevier Inc. All rights reserved.

Cardiac DPP-4 inhibition by saxagliptin ameliorates isoproterenol-induced myocardial remodeling and cardiac diastolic dysfunction in rats.

PubMed

Ikeda, Junichi; Kimoto, Naoya; Kitayama, Tetsuya; Kunori, Shunji

2016-09-01

Saxagliptin, a potent and selective DPP-4 inhibitor, is characterized by its slow dissociation from DPP-4 and its long half-life and is expected to have a potent tissue membrane-bound DPP-4-inhibitory effect in various tissues. In the present study, we examined the effects of saxagliptin on in situ cardiac DPP-4 activity. We also examined the effects of saxagliptin on isoproterenol-induced the changes in the early stage such as, myocardial remodeling and cardiac diastolic dysfunction. Male SD rats treated with isoproterenol (1 mg/kg/day via osmotic pump) received vehicle or saxagliptin (17.5 mg/kg via drinking water) for 2 weeks. In situ cardiac DPP-4 activity was measured by a colorimetric assay. Cardiac gene expressions were examined and an echocardiographic analysis was performed. Saxagliptin treatment significantly inhibited in situ cardiac DPP-4 activity and suppressed isoproterenol-induced myocardial remodeling and the expression of related genes without altering the blood glucose levels. Saxagliptin also significantly ameliorated cardiac diastolic dysfunction in isoproterenol-treated rats. In conclusion, the inhibition of DPP-4 activity in cardiac tissue by saxagliptin was associated with suppression of myocardial remodeling and cardiac diastolic dysfunction independently of its glucose-lowering action in isoproterenol-treated rats. Cardiac DPP-4 activity may contribute to myocardial remodeling in the development of heart failure. Copyright © 2016 Kyowa Hakko Kirin Co.,Ltd. Production and hosting by Elsevier B.V. All rights reserved.

Dihydromyricetin ameliorates atherosclerosis in LDL receptor deficient mice.

PubMed

Liu, Ting Ting; Zeng, Yi; Tang, Kun; Chen, XueMeng; Zhang, Wei; Xu, Xiao Le

2017-07-01

Dihydromyricetin, the most abundant flavonoid in Ampelopsis grossedentata, exerts numerous pharmacological activities, including anti-inflammatory, antioxidant, hepatoprotective, and lipid regulatory activities; however, its protective effect against atherosclerosis remains poorly understood. The aim of the present study was to evaluate the effects of dihydromyricetin on high fat diet (HFD)-induced atherosclerosis using LDL receptor deficient (LDLr -/- ) mice. Blood samples were collected for determination of serum lipid profiles, oxidized LDL (ox-LDL) and pro-inflammatory cytokines. Histology, hepatic lipid content, quantification of atherosclerosis, assessment of oxidative stress and inflammation were performed on liver and aorta samples by molecular biology methods. The effects of dihydromyricetin on ox-LDL-induced human umbilical vein endothelial cells (HUVECs) dysfunction and foam cell formation were further studied. (1) Dihydromyricetin ameliorated hyperlipidemia, reduced serum ox-LDL, IL-6 and TNF-α levels in HFD-fed LDLr -/- mice. Moreover, (2) dihydromyricetin suppressed hepatic lipid accumulation and increased protein expressions of PPARα, LXRα and ABCA1. (3) It inhibited atherosclerotic lesion formation and favoured features of plaque stability. (4) Dihydromyricetin prevented hepatic and aortic inflammation as evidenced by the reduced IL-6 and TNF-α mRNA expression; (5) it prevented hepatic and aortic oxidative stress by normalizing activities of antioxidant enzymes in the liver and suppressing reactive oxygen species generation and NOX2 protein expression in both liver and aorta; (6) it inhibited oxLDL-induced injury, monocytes adhesion and oxidative stress in HUVECs and (7) inhibited macrophage foam cell formation and enhanced cholesterol efflux. These findings suggest that dihydromyricetin could reduce atherosclerosis via its pleiotropic effects, including improvement of endothelial dysfunction, inhibition of macrophage foam cell formation

Butyrylcholinesterase inhibitors ameliorate cognitive dysfunction induced by amyloid-β peptide in mice

PubMed Central

Furukawa-Hibi, Yoko; Alkam, Tursun; Nitta, Atsumi; Matsuyama, Akihiro; Mizoguchi, Hiroyuki; Suzuki, Kazuhiko; Moussaoui, Saliha; Yu, Qian-Sheng; Greig, Nigel H.; Nagai, Taku; Yamada, Kiyofumi

2016-01-01

The cholinesterase inhibitor, rivastigmine, ameliorates cognitive dysfunction and is approved for the treatment of Alzheimer's disease (AD). Rivastigmine is a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE); however, the impact of BuChE inhibition on cognitive dysfunction remains to be determined. We compared the effects of a selective BuChE inhibitor, N1-phenethylnorcymserine (PEC), rivastigmine and donepezil (an AChE-selective inhibitor) on cognitive dysfunction induced by amyloid-β peptide (Aβ1–40) in mice. Five-week-old imprinting control region (ICR) mice were injected intracerebroventricularly (i.c.v.) with either Aβ1–40 or the control peptide Aβ40–1 on Day 0, and their recognition memory was analyzed by a novel object recognition test. Treatment with donepezil (1.0 mg/kg), rivastigmine (0.03, 0.1, 0.3 mg/kg) or PEC (1.0, 3.0 mg/kg) 20 min prior to, or immediately after the acquisition session (Day 4) ameliorated the Aβ1–40 induced memory impairment, indicating a beneficial effect on memory acquisition and consolidation. In contrast, none of the investigated drugs proved effective when administrated before the retention session (Day 5). Repeated daily administration of donepezil, rivastigmine or PEC, on Days 0–3 inclusively, ameliorated the cognitive dysfunction in Aβ1–40 challenged mice. Consistent with the reversal of memory impairments, donepezil, rivastigmine or PEC treatment significantly reduced Aβ1–40 induced tyrosine nitration of hippocampal proteins, a marker of oxidative damage. These results indicate that BuChE inhibition, as well as AChE inhibition, is a viable therapeutic strategy for cognitive dysfunction in AD. PMID:21820013

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.

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

PubMed Central

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

2017-01-01

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. PMID:28260014

Inhibition of galectin-3 ameliorates the consequences of cardiac lipotoxicity in a rat model of diet-induced obesity.

PubMed

Marín-Royo, Gema; Gallardo, Isabel; Martínez-Martínez, Ernesto; Gutiérrez, Beatriz; Jurado-López, Raquel; López-Andrés, Natalia; Gutiérrez-Tenorio, Josué; Rial, Eduardo; Bartolomé, Marı A Visitación; Nieto, María Luisa; Cachofeiro, Victoria

2018-02-05

Obesity is accompanied by metabolic alterations characterized by insulin resistance and cardiac lipotoxicity. Galectin-3 (Gal-3) induces cardiac inflammation and fibrosis in the context of obesity; however, its role in the metabolic consequences of obesity is not totally established. We have investigated the potential role of Gal-3 in the cardiac metabolic disturbances associated with obesity. In addition, we have explored whether this participation is, at least partially, acting on mitochondrial damage. Gal-3 inhibition in rats that were fed a high-fat diet (HFD) for 6 weeks with modified citrus pectin (MCP; 100 mg/kg/day) attenuated the increase in cardiac levels of total triglyceride (TG). MCP treatment also prevented the increase in cardiac protein levels of carnitine palmitoyl transferase IA, mitofusin 1, and mitochondrial complexes I and II, reactive oxygen species accumulation and decrease in those of complex V but did not affect the reduction in 18 F-fluorodeoxyglucose uptake observed in HFD rats. The exposure of cardiac myoblasts (H9c2) to palmitic acid increased the rate of respiration, mainly due to an increase in the proton leak, glycolysis, oxidative stress, β-oxidation and reduced mitochondrial membrane potential. Inhibition of Gal-3 activity was unable to affect these changes. Our findings indicate that Gal-3 inhibition attenuates some of the consequences of cardiac lipotoxicity induced by a HFD since it reduced TG and lysophosphatidyl choline (LPC) levels. These reductions were accompanied by amelioration of the mitochondrial damage observed in HFD rats, although no improvement was observed regarding insulin resistance. These findings increase the interest for Gal-3 as a potential new target for therapeutic intervention to prevent obesity-associated cardiac lipotoxicity and subsequent mitochondrial dysfunction . © 2018. Published by The Company of Biologists Ltd.

Inhibition of galectin-3 ameliorates the consequences of cardiac lipotoxicity in a rat model of diet-induced obesity

PubMed Central

Marín-Royo, Gema; Gallardo, Isabel; Martínez-Martínez, Ernesto; Gutiérrez, Beatriz; Jurado-López, Raquel; López-Andrés, Natalia; Gutiérrez-Tenorio, Josué; Rial, Eduardo; Bartolomé, María Visitación; Nieto, María Luisa

2018-01-01

ABSTRACT Obesity is accompanied by metabolic alterations characterized by insulin resistance and cardiac lipotoxicity. Galectin-3 (Gal-3) induces cardiac inflammation and fibrosis in the context of obesity; however, its role in the metabolic consequences of obesity is not totally established. We have investigated the potential role of Gal-3 in the cardiac metabolic disturbances associated with obesity. In addition, we have explored whether this participation is, at least partially, acting on mitochondrial damage. Gal-3 inhibition in rats that were fed a high-fat diet (HFD) for 6 weeks with modified citrus pectin (MCP; 100 mg/kg/day) attenuated the increase in cardiac levels of total triglyceride (TG). MCP treatment also prevented the increase in cardiac protein levels of carnitine palmitoyl transferase IA, mitofusin 1, and mitochondrial complexes I and II, reactive oxygen species accumulation and decrease in those of complex V but did not affect the reduction in 18F-fluorodeoxyglucose uptake observed in HFD rats. The exposure of cardiac myoblasts (H9c2) to palmitic acid increased the rate of respiration, mainly due to an increase in the proton leak, glycolysis, oxidative stress, β-oxidation and reduced mitochondrial membrane potential. Inhibition of Gal-3 activity was unable to affect these changes. Our findings indicate that Gal-3 inhibition attenuates some of the consequences of cardiac lipotoxicity induced by a HFD since it reduced TG and lysophosphatidyl choline (LPC) levels. These reductions were accompanied by amelioration of the mitochondrial damage observed in HFD rats, although no improvement was observed regarding insulin resistance. These findings increase the interest for Gal-3 as a potential new target for therapeutic intervention to prevent obesity-associated cardiac lipotoxicity and subsequent mitochondrial dysfunction. PMID:29361517

Inhibition of soluble epoxide hydrolase lowers portal hypertension in cirrhotic rats by ameliorating endothelial dysfunction and liver fibrosis.

PubMed

Deng, Wensheng; Zhu, Yiming; Lin, Jiayun; Zheng, Lei; Zhang, Chihao; Luo, Meng

2017-07-01

Epoxyeicostrienoic acids (EETs) are arachidonic acid derived meditators which are catalyzed by soluble epoxide hydrolase (sEH) to less active dihydroeicostrienoics acids (DHETS). The aim of our study is to investigate the effects of sEH inhibition on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl4 cirrhotic rats. The sEH inhibitor,trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]cyclohexyloxy}benzoic acid (t-TUCB) was administered to stabilize hepatic EETs by gavage at a dose of 1mg/kg/d. Our results showed that hepatic sEH expression was markedly increased in portal hypertension, and led to a lower ratio of EETs/DHETs which was effectively reversed by t-TUCB administration. t-TUCB significantly decreased portal pressure without significant changes in systemic hemodynamics, which was associated with the attenuation of intrahepatic vascular resistance (IHVR) and liver fibrosis. t-TUCB ameliorated endothelial dysfunction, increased hepatic endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production. In addition, t-TUCB significantly reduced alpha-Smooth Muscle Actin (α-SMA) expression and liver fibrosis, which was associated with a decrease in NF-κB signaling. Taken together, inhibition of sEH reduces portal pressure, liver fibrosis and attenuates hepatic endothelial dysfunction in cirrhotic rats. Our results indicate that sEH inhbitors may be useful in the treatment of portal hypertension in patients with cirrhosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Recombinant human brain natriuretic peptide ameliorates trauma-induced acute lung injury via inhibiting JAK/STAT signaling pathway in rats.

PubMed

Song, Zhi; Zhao, Xiu; Gao, Yan; Liu, Martin; Hou, Mingxiao; Jin, Hongxu; Cui, Yan

2015-05-01

JAK/STAT signal pathway plays an important role in the inflammation process of acute lung injury (ALI). This study aimed to investigate the correlation between recombinant human brain natriuretic peptide (rhBNP) and the JAK/STAT signaling pathway and to explore the protective mechanism of rhBNP against trauma-induced ALI. The arterial partial pressure in oxygen, lung wet-dry weight ratios, protein content in bronchoalveolar lavage fluid, the histopathologic of the lung, as well as the protein expressions of STAT1, JAK2, and STAT3 were detected. Sprague-Dawley rats were randomly divided into five groups: a control group, a sham-operated group, an ALI group, an ALI + rhBNP group, and an ALI + AG490 group. At 4 hours, 12 hours, 1 day, 3 days, and 7 days after injury, injured lung specimens were harvested. rhBNP pretreatment significantly ameliorated hypoxemia and histopathologic changes and alleviated pulmonary edema in trauma-induced ALI rats. rhBNP pretreatment reduced the phosphorylated protein and total protein level of STAT1. Similarly to JAK-specific inhibitor AG490, rhBNP was shown to significantly inhibit the phosphorylation of JAK2 and STAT3 in rats with trauma-induced ALI. Our experimental findings indicated that rhBNP can protect rats against trauma-induced ALI and that its underlying mechanism may be related to the inhibition of JAK/STAT signaling pathway activation.

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

PubMed

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

2016-08-12

Although 6-shogaol, a constituent of ginger, has been reported to have anti-inflammatory and anti-oxidant effects on neuronal cells, the effects of 6-shogaol on Alzheimer's disease (AD) have not yet been investigated. Here we aimed to determine whether 6-shogaol exerts neuroprotective effects against AD. Specifically, we investigated the effects of 6-shogaol on the cysteinyl leukotriene 1 receptor (CysLT1R), a major factor in AD pathogenesis. Moreover, we clarified the relationship between CysLT1R and cathepsin B, a cysteine protease. We used in vitro and in vivo models to determine whether 6-shogaol inhibits CysLT1R/cathepsin B in an amyloid-beta (Aβ; 1-42)-induced model of neurotoxicity. We first confirmed that CysLT1R and cathepsin B are upregulated by Aβ (1-42) and that CysLT1R activation induces cathepsin B. In contrast, we found that 6-shogaol-mediated inhibition of CysLT1R downregulates cathepsin B in both in vitro and in vivo models. Furthermore, we found that 6-shogaol-mediated inhibition of CysLT1R/cathepsin B reduces Aβ deposition in the brain and ameliorates behavioral deficits in APPSw/PS1-dE9 Tg mice. Our results indicate that 6-shogaol is a CysLT1R/cathepsin B inhibitor and is a novel potential therapeutic agent for the treatment of various neurodegenerative diseases, including AD. Copyright © 2016 Elsevier Inc. All rights reserved.

Formononetin ameliorates mast cell-mediated allergic inflammation via inhibition of histamine release and production of pro-inflammatory cytokines

PubMed Central

Xu, Ning; An, Jun

2017-01-01

Various allergic diseases cause allergic inflammation, which is mediated by mast cells. The current study investigated the anti-allergic inflammatory effects of formononetin and its mechanism of action in vitro using mast cells. Levels of histamine and pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6, were measured to assess the effects of formononetin on allergic inflammation. The activation of intracellular calcium and nuclear factor (NF)-κB, as well as the activity of caspase-1, were assessed to determine the mechanism of action. It was determined that difference concentrations of formononetin (0.1, 1 and 10 µM) suppressed histamine release and secretion of TNF-α, IL-1β and IL-6. Further investigations indicated that the effects of formononetin were associated with a reduction of intracellular calcium, suppression of NF-κB activation and upstream IκKα phosphorylation and inhibition of caspase-1 activity. Therefore, the results of the current study demonstrated that formononetin ameliorated mast cell-mediated allergic inflammation. PMID:29250144

Formononetin ameliorates mast cell-mediated allergic inflammation via inhibition of histamine release and production of pro-inflammatory cytokines.

PubMed

Xu, Ning; An, Jun

2017-12-01

Various allergic diseases cause allergic inflammation, which is mediated by mast cells. The current study investigated the anti-allergic inflammatory effects of formononetin and its mechanism of action in vitro using mast cells. Levels of histamine and pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6, were measured to assess the effects of formononetin on allergic inflammation. The activation of intracellular calcium and nuclear factor (NF)-κB, as well as the activity of caspase-1, were assessed to determine the mechanism of action. It was determined that difference concentrations of formononetin (0.1, 1 and 10 µM) suppressed histamine release and secretion of TNF-α, IL-1β and IL-6. Further investigations indicated that the effects of formononetin were associated with a reduction of intracellular calcium, suppression of NF-κB activation and upstream IκKα phosphorylation and inhibition of caspase-1 activity. Therefore, the results of the current study demonstrated that formononetin ameliorated mast cell-mediated allergic inflammation.

Nobiletin and tangeretin ameliorate scratching behavior in mice by inhibiting the action of histamine and the activation of NF-κB, AP-1 and p38.

PubMed

Jang, Se-Eun; Ryu, Kwon-Ryeol; Park, Sung-Hwan; Chung, Suna; Teruya, Yuto; Han, Myung Joo; Woo, Je-Tae; Kim, Dong-Hyun

2013-11-01

Nobiletin and tangeretin are polymethoxy flavonoids that are abundantly present in the pericarp of Citrus unshiu (family Rutaceae) and the fruit of Citrus depressa (family Rutaceae). They exhibit various biological activities, including anti-inflammatory and anti-asthmatic effects. To evaluate the anti-allergic effects of nobiletin and tangeretin, we measured their inhibitory effects in histamine- or compound 48/80-induced scratching behavioral mice. Nobiletin and tangeretin potently inhibited scratching behavior, as well as histamine-induced vascular permeability. Furthermore, they inhibited the expression of the allergic cytokines, IL-4 and TNF-α as well as the activation of their transcription factors NF-κB, AP-1 and p38 in histamine-stimulated skin tissues. They also inhibited the expression of IL-4 and TNF-α and the activation of NF-κB and c-jun in PMA-stimulated RBL-2H3 cells. Furthermore, nobiletin and tangeretin inhibited protein kinase C (PKC) activity and the IgE-induced degranulation of RBL-2H3 cells. These agents showed potent anti-histamine effect through the Magnus test when guinea pig ileum was used. Based on these results, nobiletin and tangeretin may ameliorate scratching behavioral reactions by inhibiting the action of histamine as well as the activation of the transcription factors NF-κB and AP-1 via PKC. © 2013.

Inhibition of 5a-reductase in the nucleus accumbens counters sensorimotor gating deficits induced by dopaminergic activation

PubMed Central

Devoto, Paola; Frau, Roberto; Bini, Valentina; Pillolla, Giuliano; Saba, Pierluigi; Flore, Giovanna; Corona, Marta; Marrosu, Francesco; Bortolato, Marco

2012-01-01

Summary Cogent evidence highlights a key role of neurosteroids and androgens in schizophrenia. We recently reported that inhibition of steroid 5α-reductase (5αR), the rate-limiting enzyme in neurosteroid synthesis and androgen metabolism, elicits antipsychotic-like effects in humans and animal models, without inducing extrapyramidal side effects. To elucidate the anatomical substrates mediating these effects, we investigated the contribution of peripheral and neural structures to the behavioral effects of the 5αR inhibitor finasteride (FIN) on the prepulse inhibition (PPI) of the acoustic startle reflex (ASR), a rat paradigm that dependably simulates the sensorimotor gating impairments observed in schizophrenia and other neuropsychiatric disorders. The potential effect of drug-induced ASR modifications on PPI was excluded by measuring this index both as percent (%PPI) and absolute values (ΔPPI). In both orchidectomized and sham-operated rats, FIN prevented the %PPI deficits induced by the dopamine (DA) receptor agonists apomorphine (APO, 0.25 mg/kg, SC) and d-amphetamine (AMPH, 2.5 mg/kg, SC), although the latter effect was not corroborated by ΔPPI analysis. Conversely, APO-induced PPI deficits were countered by FIN infusions in the brain ventricles (10 μg/1 μl) and in the nucleus accumbens (NAc) shell and core (0.5 μg/0.5 μl/side). No significant PPI-ameliorating effect was observed following FIN injections in other brain regions, including dorsal caudate, basolateral amygdala, ventral hippocampus and medial prefrontal cortex, although a statistical trend was observed for the latter region. The efflux of DA in NAc was increased by systemic, but not intracerebral FIN administration. Taken together, these findings suggest that the role of 5αR in gating regulation is based on post-synaptic mechanisms in the NAc, and is not directly related to alterations in DA efflux in this region. PMID:22029952

Epigallocatechin-3-gallate Ameliorates Seawater Aspiration-Induced Acute Lung Injury via Regulating Inflammatory Cytokines and Inhibiting JAK/STAT1 Pathway in Rats

PubMed Central

Liu, Wei; Dong, Mingqing; Bo, Liyan; Li, Congcong; Liu, Qingqing; Li, Yanyan; Ma, Lijie; Xie, Yonghong; Fu, Enqing; Mu, Deguang; Pan, Lei; Jin, Faguang; Li, Zhichao

2014-01-01

Signal transducers and activators of transcriptions 1 (STAT1) play an important role in the inflammation process of acute lung injury (ALI). Epigallocatechin-3-gallate (EGCG) exhibits a specific and strong anti-STAT1 activity. Therefore, our study is to explore whether EGCG pretreatment can ameliorate seawater aspiration-induced ALI and its possible mechanisms. We detected the arterial partial pressure of oxygen, lung wet/dry weight ratios, protein content in bronchoalveolar lavage fluid, and the histopathologic and ultrastructure staining of the lung. The levels of IL-1, TNF-α, and IL-10 and the total and the phosphorylated protein level of STAT1, JAK1, and JAK2 were assessed in vitro and in vivo. The results showed that EGCG pretreatment significantly improved hypoxemia and histopathologic changes, alleviated pulmonary edema and lung vascular leak, reduced the production of TNF-α and IL-1, and increased the production of IL-10 in seawater aspiration-induced ALI rats. EGCG also prevented the seawater aspiration-induced increase of TNF-α and IL-1 and decrease of IL-10 in NR8383 cell line. Moreover, EGCG pretreatment reduced the total and the phosphorylated protein level of STAT1 in vivo and in vitro and reduced the phosphorylated protein level of JAK1 and JAK2. The present study demonstrates that EGCG ameliorates seawater aspiration-induced ALI via regulating inflammatory cytokines and inhibiting JAK/STAT1 pathway in rats. PMID:24692852

Ma Huang Tang ameliorates asthma though modulation of Th1/Th2 cytokines and inhibition of Th17 cells in ovalbumin-sensitized mice.

PubMed

Ma, Chun-Hua; Ma, Zhan-Qiang; Fu, Qiang; Ma, Shi-Ping

2014-05-01

Ma Huang Tang (Ephedra decoction, MHT) is a famous classical formula from Shang Han Lun by Zhang Zhongjing in the Han Dynasty. The anti-asthmatic effects of MHT and the possible mechanisms were tested. An asthma model was established by ovalbumin (OVA)-induction in mice. A total of forty-eight mice were randomly assigned to six experimental groups: control, model, dexamethasone (2 mg·kg(-1)) and MHT (5, 10, and 20 mg·kg(-1)). Airway resistance (Raw) was measured by the forced oscillation technique, histological studies were evaluated by hematoxylin and eosin (HE) staining, Th1/Th2 and Th17 cytokines were evaluated by enzyme-linked immunosorbent assay (ELISA), and Th17 cells were evaluated by flow cytometry (FCM). This study demonstrated that MHT inhibited OVA-induced increases in Raw and eosinophil count; interleukin (IL)-4 and IL-17 levels were recovered in bronchoalveolar lavage fluid, increased IFN-γ level in bronchoalveolar lavage fluid. Histological studies demonstrated that MHT substantially inhibited OVA-induced eosinophilia in lung tissue. Flow cytometry studies demonstrated that MHT substantially inhibited Th17 cells. These findings suggest that MHT may effectively ameliorate the progression of asthma, and could be further investigated for potential use as a therapy for patients with allergic asthma. Copyright © 2014 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

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

PubMed Central

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

2009-01-01

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

Administration of Menadione, Vitamin K3, Ameliorates Off-Target Effects on Corneal Epithelial Wound Healing Due to Receptor Tyrosine Kinase Inhibition.

PubMed

Rush, Jamie S; Bingaman, David P; Chaney, Paul G; Wax, Martin B; Ceresa, Brian P

2016-11-01

The antiangiogenic receptor tyrosine kinase inhibitor (RTKi), 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-[[[[4-(1-pyrrolidinyl) butyl] amino] carbonyl]amino]-4-isothiazolecarboxamide hydrochloride, targets VEGFR2 (half maximal inhibitory concentration [IC50] = 11 nM); however, off-target inhibition of epidermal growth factor receptor (EGFR) occurs at higher concentrations. (IC50 = 5.8 μM). This study was designed to determine the effect of topical RTKi treatment on EGF-mediated corneal epithelial wound healing and to develop new strategies to minimize off-target EGFR inhibition. In vitro corneal epithelial wound healing was measured in response to EGF using a transformed human cell line (hTCEpi cells). In vivo corneal wound healing was assessed using a murine model. In these complementary assays, wound healing was measured in the presence of varying RTKi concentrations. Immunoblot analysis was used to examine EGFR and VEGFR2 phosphorylation and the kinetics of EGFR degradation. An Alamar Blue assay measured VEGFR2-mediated cell biology. Receptor tyrosine kinase inhibitor exposure caused dose-dependent inhibition of EGFR-mediated corneal epithelial wound healing in vitro and in vivo. Nanomolar concentrations of menadione, a vitamin K3 analog, when coadministered with the RTKi, slowed EGFR degradation and ameliorated the inhibitory effects on epithelial wound healing both in vitro and in vivo. Menadione did not alter the RTKi's IC50 against VEGFR2 phosphorylation or its inhibition of VEGF-induced retinal endothelial cell proliferation. An antiangiogenic RTKi exhibited off-target effects on the corneal epithelium that can be minimized by menadione without deleteriously affecting its on-target VEGFR2 blockade. These data indicate that menadione has potential as a topical supplement for individuals suffering from perturbations in corneal epithelial homeostasis, especially as an untoward side effect of kinase inhibitors.

Curcumin ameliorates cardiac dysfunction induced by mechanical trauma.

PubMed

Li, Xintao; Cao, Tingting; Ma, Shuo; Jing, Zehao; Bi, Yue; Zhou, Jicheng; Chen, Chong; Yu, Deqin; Zhu, Liang; Li, Shuzhuang

2017-11-05

Curcumin, a phytochemical component derived from turmeric (Carcuma longa), has been extensively investigated because of its anti-inflammatory and anti-oxidative properties. Inflammation and oxidative stress play critical roles in posttraumatic cardiomyocyte apoptosis, which contributes to secondary cardiac dysfunction. This research was designed to identify the protective effect of curcumin on posttraumatic cardiac dysfunction and investigate its underlying mechanism. Noble-Collip drum was used to prepare a mechanical trauma (MT) model of rats, and the hemodynamic responses of traumatized rats were observed by ventricular intubation 12h after trauma. Myocardial apoptosis was determined through terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and caspase-3 activity assay. Tumor necrosis factor-α (TNF-α) and reactive oxygen species (ROS) generated by monocytes and myocardial cells were identified through enzyme-linked immunosorbent assay (ELISA), and the intracellular alteration of Ca 2+ in cardiomyocytes was examined through confocal microscopy. In vivo, curcumin effectively ameliorated MT-induced secondary cardiac dysfunction and significantly decreased the apoptotic indices of the traumatized myocardial cells. In vitro, curcumin inhibited TNF-α production by monocytes and reduced the circulating TNF-α levels. With curcumin pretreatment, ROS production and Ca 2+ overload in H9c2 cells were attenuated when these cells were incubated with traumatic plasma. Therefore, curcumin can effectively ameliorate MT-induced cardiac dysfunction mainly by inhibiting systemic inflammatory responses and by weakening oxidative stress reaction and Ca 2+ overload in cardiomyocytes. Copyright © 2017 Elsevier B.V. All rights reserved.

GLYX-13 Ameliorates Schizophrenia-Like Phenotype Induced by MK-801 in Mice: Role of Hippocampal NR2B and DISC1

PubMed Central

Zhou, Dongsheng; Lv, Dan; Wang, Zhen; Zhang, Yanhua; Chen, Zhongming; Wang, Chuang

2018-01-01

Background: Evidence supports that the hypofunction of N-methyl-D-aspartate receptor (NMDAR) and downregulation of disrupted-in-schizophrenia 1 (DISC1) contribute to the pathophysiology of schizophrenia. N-Methyl D-aspartate receptor subtype 2B (NR2B)-containing NMDAR are associated with cognitive dysfunction in schizophrenia. GLYX-13 is an NMDAR glycine-site functional partial agonist and cognitive enhancer that does not induce psychotomimetic side effects. However, it remains unclear whether NR2B plays a critical role in the GLYX-13-induced alleviation of schizophrenia-like behaviors in mice. Methods: The effect of GLYX-13 was tested by observing changes in locomotor activity, novel object recognition ability, and prepulse inhibition (PPI) induced by dizocilpine (known as MK-801) in mice. Lentivirus-mediated NR2B knockdown in the hippocampus was assessed to confirm the role of NR2B in GLYX-13 pathophysiology, using Western blots and immunohistochemistry. Results: The systemic administration of GLYX-13 (0.5 and 1 mg/kg, i.p.) ameliorates MK-801 (0.5 mg/kg, i.p.)-induced hyperlocomotion, deficits in memory, and PPI in mice. Additionally, GLYX-13 normalized the MK-801-induced alterations in signaling molecules, including NR2B and DISC1 in the hippocampus. Furthermore, we found that NR2B knockdown produced memory and PPI deficits without any changes in locomotor activity. Notably, DISC1 levels significantly decreased by NR2B knockdown. However, the effective dose of GLYX-13 did not alleviate the memory and PPI dysfunctions or downregulation of DISC1 induced by NR2B knockdown. Conclusion: Our results suggest GLYX-13 as a candidate for schizophrenia treatment, and NR2B and DISC1 in the hippocampus may account for the molecular mechanisms of GLYX-13. PMID:29695955

Ala42S100A8 Ameliorates Psychological-Stress Impaired Cutaneous Wound Healing

PubMed Central

Sroussi, Herve Y.; Williams, Richard L.; Zhang, Qing. L.; Villines, Dana.; Marucha, Phillip. T.

2009-01-01

Although wound healing is generally a successful, carefully orchestrated and evolutionary sound process, it can be disregulated by extrinsic factors such as psychological stress. In the SKH-1 restraint stress model of cutaneous wound healing, the rate of wound closure is approximately 30% slower in stressed mice. Delay in healing is associated with exaggerated acute inflammation and deficient bacterial clearance at the wound site. It has been suggested that wound hypoxia may contribute to the mechanisms of impaired cutaneous wound healing in the mouse SKH-1 model. Optimal healing of a cutaneous wound is a stepwise repair program. In its early phase, an inflammatory oxidative burst generated by neutrophils is observed. 40% of neutrophils cytosolic protein weight is comprised of two calcium binding proteins S100A8 and S100A9. Our previous work has shown that S100A8 act as an oxidation sensitive repellent of human neutrophils in-vitro. Ala42S100A8, a site-directed mutant protein is resistant to oxidative inhibition and inhibits neutrophil recruitment in-vivo. Accordingly, we tested the hypothesis that S100A8 may ameliorate wound healing in this model. We examined the effect of wild type and ala42S100A8 for their ability to ameliorate wound closure rates. The data indicated that a single local application of ala42S100A8 ameliorated the decreased rate of wound closure resulting from stress. This occurred without significantly affecting wound bacterial clearance. Wild type S100A8 only had a partial beneficial effect on the rate of wound closure. Those findings support further translational studies of S100 based intervention to ameliorate impaired wound healing. PMID:19336252

Ala42S100A8 ameliorates psychological-stress impaired cutaneous wound healing.

PubMed

Sroussi, Herve Y; Williams, Richard L; Zhang, Qing L; Villines, Dana; Marucha, Phillip T

2009-08-01

Although wound healing is generally a successful, carefully orchestrated and evolutionary sound process, it can be disregulated by extrinsic factors such as psychological-stress. In the SKH-1 restraint stress model of cutaneous wound healing, the rate of wound closure is approximately 30% slower in stressed mice. Delay in healing is associated with exaggerated acute inflammation and deficient bacterial clearance at the wound site. It has been suggested that wound hypoxia may contribute to the mechanisms of impaired cutaneous wound healing in the mouse SKH-1 model. Optimal healing of a cutaneous wound is a stepwise repair program. In its early phase, an inflammatory oxidative burst generated by neutrophils is observed. About 40% of neutrophils cytosolic protein weight is comprised of two calcium binding proteins S100A8 and S100A9. Our previous work has shown that S100A8 act as an oxidation-sensitive repellent of human neutrophils in-vitro. Ala(42)S100A8, a site-directed mutant protein is resistant to oxidative inhibition and inhibits neutrophil recruitment in-vivo. Accordingly, we tested the hypothesis that S100A8 may ameliorate wound healing in this model. We examined the effect of wild-type and ala(42)S100A8 for their ability to ameliorate wound closure rates. The data indicated that a single local application of ala(42)S100A8 ameliorated the decreased rate of wound closure resulting from stress. This occurred without significantly affecting wound bacterial clearance. Wild-type S100A8 only had a partial beneficial effect on the rate of wound closure. Those findings support further translational studies of S100 based intervention to ameliorate impaired wound healing.

Investigation of Zn and Cu prepulse plasmas relevant to collisional excitation x-ray lasers

NASA Astrophysics Data System (ADS)

Rus, B.; Zeitoun, P.; Mocek, T.; Sebban, S.; Kálal, M.; Demir, A.; Jamelot, G.; Klisnick, A.; Králiková, B.; Skála, J.; Tallents, G. J.

1997-11-01

This paper presents the results of a comparative experimental study of low-temperature Zn and Cu line plasmas created on slab targets by 400-ps laser pulse producing irradiance from 4×109 to 1011 W cm-2. The aim was to examine the nanosecond-scale postpulse evolution of plasmas created in conditions equivalent to those produced by prepulses in collisional x-ray lasers, of elements that have neighboring atomic numbers but very different material properties. The plasmas were interferometrically probed at 4 and 10 ns next to the driving pulse, using geometry that made it possible to obtain an authentic two-dimensional (2D) electron density pattern in the plane perpendicular to the plasma axis. VIS-IR spectroscopy and imaging were used to provide an indication of the electron temperature and volume of the plasma layer near the target. We observe that over the whole range of the applied irradiances the characteristics and/or the expansion history of the Zn and Cu plasmas are very different. For irradiance exceeding a threshold specific to each element the density patterns exhibit an unexpected structure characterized by symmetrical flanks strongly localized in space, suggesting plasma is generated in addition to that produced within the laser pulse duration. The results imply that during the postpulse time the energy coupling between the plasma and the target is substantial for the plasma flow that exhibits a complex 2D character. A comparison of the data and results of a 1.5D hydrodynamic simulation for 1011 W cm-2 is made, indicating reasons for problems of such models in the treatment of the plasmas in question, and thus in the treatment of small-prepulse action in some x-ray laser systems.

Hydrogen sulfide ameliorates subarachnoid hemorrhage-induced neuronal apoptosis via the ROS-MST1 pathway

PubMed Central

Shi, Ligen; Lei, Jianwei; Xu, Hangzhe; Zheng, Jingwei; Wang, Yan; Peng, Yucong; Yu, Jun; Zhang, Jianmin

2017-01-01

Background Hydrogen sulfide (H2S) has shown a neuroprotective role in several cerebrovascular diseases. This study aimed to explore the underlying mechanisms of H2S in early brain injury after subarachnoid hemorrhage (SAH). Methods One hundred seventy-seven male Sprague-Dawley rats were employed in this study. Sodium hydrosulfide (NaHS), a donor of H2S, was injected intraperitoneally at 60 min after SAH was induced by endovascular perforation. Western blot analysis determined the expression of several proteins of interest, and an immunofluorescence assay was used to examine neuronal apoptosis. Results Exogenous NaHS markedly improved neurological scores, attenuated brain edema, and ameliorated neuronal apoptosis at 24 h after SAH induction. The underlying mechanisms of H2S in ameliorating neuronal apoptosis might be executed through inhibition of the activity of mammalian sterile 20-like kinase 1 (MST1) protein. Western blot analysis demonstrated that exogenous NaHS decreased cleaved MST1 (cl-MST1) while increasing full-length MST1 expression. This anti-apoptotic effect of H2S could be reversed by chelerythrine, which could activate MST1 via caspase-dependent cleavage. Conclusions Exogenous NaHS, as a donor of H2S, could ameliorate early brain injury after SAH by inhibiting neuronal apoptosis by reducing the activity of the MST1 protein. PMID:29088725

High molecular weight polysaccharide that binds and inhibits virus

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

Konowalchuk, Thomas W.; Konowalchuk, Jack

This invention provides a high molecular weight polysaccharide capable of binding to and inhibiting virus and related pharmaceutical formulations and methods of inhibiting viral infectivity and/or pathogenicity, as well as immunogenic compositions. The invention further includes 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.

High molecular weight polysaccharide that binds and inhibits virus

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

Konowalchuk, Thomas W

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.

Caffeic Acid Phenethyl Ester (Propolis Extract) Ameliorates Insulin Resistance by Inhibiting JNK and NF-κB Inflammatory Pathways in Diabetic Mice and HepG2 Cell Models.

PubMed

Nie, Jiarui; Chang, Yaning; Li, Yujia; Zhou, Yingjun; Qin, Jiawen; Sun, Zhen; Li, Haibin

2017-10-18

Caffeic acid phenethyl ester (CAPE), extracted from propolis, was evaluated for the ameliorative effects on insulin resistance and the mechanisms were identified, using non-insulin-dependent diabetes mellitus (NIDDM) model mice and insulin resistance (IR) model cells. After 5 weeks of CAPE supplementation, insulin sensitivity, hyperlipidemia, and peroxisome proliferator-activated receptor-α (PPAR-α) levels were improved in mice. Proinflammatory cytokines in serum and the expressions of tumor necrosis factor-alpha (TNF-α) mRNA in tissues were markedly downregulated from CAPE-treated mice. In vitro, CAPE supplement significantly improved glucose consumption, glucose uptake, glycogen content, and oxidative stress and decreased expression of glucose-6-phosphatase (G6Pase) mRNA in cells. Both in vivo and in vitro, CAPE enhanced p-Akt (Ser473) and p-insulin receptor substrate (IRS)-1 (Tyr612), but inhibited p-JNK (Thr183/Tyr185), p-NF-κB p65 (Ser536), and nuclear translocation of p-NF-κB p65 (Ser536). In summary, CAPE can ameliorate insulin resistance through modulation of JNK and NF-κB signaling pathway in mice and HepG2 cells.

MitoPark mice, an animal model of Parkinson's disease, show enhanced prepulse inhibition of acoustic startle and no loss of gating in response to the adenosine A(2A) antagonist SCH 412348.

PubMed

Grauer, Steven M; Hodgson, Robert; Hyde, Lynn A

2014-04-01

Psychoses are debilitating side effects associated with current dopaminergic treatments for Parkinson's disease (PD). Prepulse inhibition (PPI), in which a non-startling stimulus reduces startle response to a subsequent startle-eliciting stimulus, is important in filtering out extraneous sensory stimuli. PPI deficits induced by dopamine agonists can model symptoms of psychosis. Adenosine A(2A) receptor antagonists, being developed as novel PD treatments, indirectly modulate dopamine signaling in the basal ganglia and may have an improved psychosis profile which could be detected using the PPI model. The aims of this study is to characterize PPI in MitoPark mice, which exhibit progressive loss of dopamine signaling and develop a Parkinson-like motor phenotype, and assess standard and novel PD treatment effects on PPI in MitoPark mice, which more closely mimic the basal ganglia dopamine status of PD patients. MitoPark mice displayed enhanced PPI as dopamine tone decreased with age, consistent with studies in intact mice that show enhanced PPI in response to dopamine antagonists. Paradoxically, older MitoParks were more sensitive to PPI disruption when challenged with dopamine agonists such as apomorphine or pramipexole. Alternatively, SCH 412348, an adenosine A(2A) antagonist, did not disrupt PPI in MitoPark mice at doses that normalized hypoactivity. Use of MitoPark mice in the PPI assay to assess the potential for PD treatment to produce psychoses likely represents a more disease-relevant model. SCH 412348 does not differentially disrupt PPI as do dopamine agonists, perhaps indicative of an improved psychosis profile of adenosine A(2A) antagonists, even in PD patients with decreased dopamine tone in the basal ganglia.

C66 ameliorates diabetic nephropathy in mice by both upregulating NRF2 function via increase in miR-200a and inhibiting miR-21

PubMed Central

Wu, Hao; Kong, Lili; Tan, Yi; Epstein, Paul N.; Zeng, Jun; Gu, Junlian; Liang, Guang; Kong, Maiying; Chen, Xiangmei

2017-01-01

Aims/hypothesis Diabetic nephropathy is the leading cause of end-stage renal disease. Previously we reported that C66, a novel analogue of curcumin with a very high bioavailability, ameliorated diabetic nephropathy in mice, with little known about the mechanism. The present study aimed to define the mechanism by which C66 ameliorates diabetic nephropathy. Methods Our aim was to discover whether C66 acts through the activation of nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or NRF2), which governs the antioxidant response. Streptozotocin-induced Nrf2 (also known as Nfe2l2)-knockout and wild-type (WT) diabetic mice were treated with C66. To determine whether the actions of C66 on NRF2 are mediated by microRNA (miR)-200a, WT diabetic mice were treated with C66 in the presence or absence of an in vivo miR-200a inhibitor (locked nucleic acid-modified anti-miR-200a [LNA-200a]) for 6 months. To determine whether miR-21 downregulation provided an NRF2-independent basis for C66 protection, Nrf2-knockout diabetic mice were treated with either C66 or an inhibitor of miR-21 (locked nucleic acid-modified anti-miR-21 [LNA-21]). Results Deletion of Nrf2 partially abolished diabetic nephropathy protection by C66, confirming the requirement of NRF2 for this protection. Diabetic mice, but not C66-treated diabetic mice, developed significant albuminuria, renal oxidative damage and fibrosis. C66 upregulated renal miR-200a, inhibited kelch-like ECH-associated protein 1 and induced NRF2 function, effects that were prevented by LNA-200a. However, LNA-200a only partially reduced the protection afforded by C66, suggesting the existence of miR-200a/NRF2-independent mechanisms for C66 protection. C66 was also found to inhibit diabetes induction of miR-21. Both C66 and LNA-21 produced similar reductions in miR-21, albuminuria and renal fibrosis. Conclusions/interpretation The present study indicates that in addition to upregulating NRF2 by increasing miR-200a, C66 also protects against

Berberine ameliorates diabetic nephropathy by inhibiting TLR4/NF-κB pathway.

PubMed

Zhu, Liping; Han, Jiakai; Yuan, Rongrong; Xue, Lei; Pang, Wuyan

2018-03-31

Diabetic nephropathy (DN) is the leading cause of end-stage renal failure, contributing to severe morbidity and mortality in diabetic patients. Berberine (BBR) has been well characterized to exert renoprotective effects in DN progression. However, the action mechanism of BBR in DN remains to be fully understood. The DN rat model was generated by intraperitoneal injection of streptozotocin (STZ, 65 mg/kg body weight) while 30 mM high glucose (HG)-treated podocytes were used as an in vitro DN model. The fasting blood glucose level and ratio of kidney weight to body weight were measured after BBR treatment (50, 100, or 200 mg/kg) in STZ-induced DN rats. The renal injury parameters including 24-h urinary protein, blood urea nitrogen and serum creatinine were assessed. qRT-PCR was performed to detect the transcript amounts of inflammatory factors. The concentrations of inflammatory factors were evaluated by ELISA kits. Western blot analysis was conducted to measure the amounts of TLR4/NF-κB-related proteins. The apoptotic rate of podocytes was analyzed by flow cytometry using Annexin V/propidium iodide. Berberine reduced renal injury in STZ-induced DN rat model, as evidenced by the decrease in fasting blood glucose, ratio of kidney weight to body weight, 24-h urinary protein, serum creatinine, and blood urine nitrogen. BBR attenuated the systemic and renal cortex inflammatory response and inhibited TLR4/NF-κB pathway in STZ-induced DN rats and HG-induced podocytes. Also, HG-induced apoptosis of podocytes was lowered by BBR administration. Furthermore, blockade of TLR4/NF-κB pathway by resatorvid (TAK-242) or pyrrolidine dithiocarbamate aggravated the inhibitory effect of BBR on HG-induced inflammatory response and apoptosis in podocytes. Berberine ameliorated DN through relieving STZ-induced renal injury, inflammatory response, and podocyte HG-induced apoptosis via inactivating TLR4/NF-κB pathway.

Inhibition of CD147 (Cluster of Differentiation 147) Ameliorates Acute Ischemic Stroke in Mice by Reducing Thromboinflammation.

PubMed

Jin, Rong; Xiao, Adam Y; Chen, Rui; Granger, D Neil; Li, Guohong

2017-12-01

Inflammation and thrombosis currently are recognized as critical contributors to the pathogenesis of ischemic stroke. CD147 (cluster of differentiation 147), also known as extracellular matrix metalloproteinase inducer, can function as a key mediator of inflammatory and immune responses. CD147 expression is increased in the brain after cerebral ischemia, but its role in the pathogenesis of ischemic stroke remains unknown. In this study, we show that CD147 acts as a key player in ischemic stroke by driving thrombotic and inflammatory responses. Focal cerebral ischemia was induced in C57BL/6 mice by a 60-minute transient middle cerebral artery occlusion. Animals were treated with anti-CD147 function-blocking antibody (αCD147) or isotype control antibody. Blood-brain barrier permeability, thrombus formation, and microvascular patency were assessed 24 hours after ischemia. Infarct size, neurological deficits, and inflammatory cells invaded in the brain were assessed 72 hours after ischemia. CD147 expression was rapidly increased in ischemic brain endothelium after transient middle cerebral artery occlusion. Inhibition of CD147 reduced infarct size and improved functional outcome on day 3 after transient middle cerebral artery occlusion. The neuroprotective effects were associated with (1) prevented blood-brain barrier damage, (2) decreased intravascular fibrin and platelet deposition, which in turn reduced thrombosis and increased cerebral perfusion, and (3) reduced brain inflammatory cell infiltration. The underlying mechanism may include reduced NF-κB (nuclear factor κB) activation, MMP-9 (matrix metalloproteinase-9) activity, and PAI-1 (plasminogen activator inhibitor-1) expression in brain microvascular endothelial cells. Inhibition of CD147 ameliorates acute ischemic stroke by reducing thromboinflammation. CD147 might represent a novel and promising therapeutic target for ischemic stroke and possibly other thromboinflammatory disorders. © 2017 American Heart

Simvastatin inhibits ox-LDL-induced inflammatory adipokines secretion via amelioration of ER stress in 3T3-L1 adipocyte.

PubMed

Wu, Zhi-hong; Chen, Ya-qin; Zhao, Shui-ping

2013-03-08

Adipocytes behave as a rich source of pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein 1 (MCP-1). Endoplasmic reticulum (ER) stress in adipocytes can alter adipokines secretion and induce inflammation. The aim of this study is to evaluate the effect of simvastatin on the ox-LDL-induced ER stress and expression and secretion of TNF-α and MCP-1 in 3T3-L1 adipocytes. Differentiated adipocytes were treated with various concentrations of ox-LDL (0-100 μg/ml) for 24h with or without simvastatin pre-treatment. The protein expressions of ER stress markers, glucose-regulated protein 78 (GRP78) and C/EBP homology protein (CHOP), were determined by Western blot analysis. The mRNA expressions of TNF-α and MCP-1 were measured by real-time PCR. The protein release of TNF-α and MCP-1 in culture medium were evaluated by ELISA. Ox-LDL treatment led to significant up-regulation of GRP78 and CHOP in dose-dependent manner. The expressions of TNF-α and MCP-1 were dose-dependently increased at mRNA and protein levels after ox-LDL intervention. The effects of ox-LDL on adipocytes were abolished by pre-treatment with 4-phenylbutyrate (4-PBA), a chemical chaperone known to ameliorate ER stress. Simvastatin could inhibit ox-LDL-induced ER stress and reduce the expression of TNF-α and MCP-1 at mRNA and protien level in dose dependent manner. In conclusion, ox-LDL can stimulate the expression and secretion of TNF-α and MCP-1 through its activation of ER stress in adipocytes. Simvastatin might exert direct anti-inflammatory effects in adipocytes through amelioration of ER stress. Copyright © 2013 Elsevier Inc. All rights reserved.

GluN2C/GluN2D subunit-selective NMDA receptor potentiator CIQ reverses MK-801-induced impairment in prepulse inhibition and working memory in Y-maze test in mice

PubMed Central

Suryavanshi, P S; Ugale, R R; Yilmazer-Hanke, D; Stairs, D J; Dravid, S M

2014-01-01

Background and Purpose Despite ample evidence supporting the N-methyl-d-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia, progress in the development of effective therapeutics based on this hypothesis has been limited. Facilitation of NMDA receptor function by co-agonists (d-serine or glycine) only partially alleviates the symptoms in schizophrenia; other means to facilitate NMDA receptors are required. NMDA receptor sub-types differ in their subunit composition, with varied GluN2 subunits (GluN2A-GluN2D) imparting different physiological, biochemical and pharmacological properties. CIQ is a positive allosteric modulator that is selective for GluN2C/GluN2D-containing NMDA receptors (Mullasseril et al.). Experimental Approach The effect of systemic administration of CIQ was tested on impairment in prepulse inhibition (PPI), hyperlocomotion and stereotypy induced by i.p. administration of MK-801 and methamphetamine. The effect of CIQ was also tested on MK-801-induced impairment in working memory in Y-maze spontaneous alternation test. Key Results We found that systemic administration of CIQ (20 mg·kg−1, i.p.) in mice reversed MK-801 (0.15 mg·kg−1, i.p.)-induced, but not methamphetamine (3 mg·kg−1, i.p.)-induced, deficit in PPI. MK-801 increased the startle amplitude to pulse alone, which was not reversed by CIQ. In contrast, methamphetamine reduced the startle amplitude to pulse alone, which was reversed by CIQ. CIQ also partially attenuated MK-801- and methamphetamine-induced hyperlocomotion and stereotyped behaviours. Additionally, CIQ reversed the MK-801-induced working memory deficit in spontaneous alternation in a Y-maze. Conclusion and Implications Together, these results suggest that facilitation of GluN2C/GluN2D-containing receptors may serve as an important therapeutic strategy for treating positive and cognitive symptoms in schizophrenia. PMID:24236947

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. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

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.

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. Copyright © 2013 Elsevier B.V. All rights reserved.

Uncaria rhynchophylla Ameliorates Parkinson's Disease by Inhibiting HSP90 Expression: Insights from Quantitative Proteomics.

PubMed

Lan, Yu-Long; Zhou, Jun-Jun; Liu, Jing; Huo, Xiao-Kui; Wang, Ya-Li; Liang, Jia-Hao; Zhao, Jian-Chao; Sun, Cheng-Peng; Yu, Zhen-Long; Fang, Lin-Lin; Tian, Xiang-Ge; Feng, Lei; Ning, Jing; Zhang, Bao-Jing; Wang, Chao; Zhao, Xin-Yu; Ma, Xiao-Chi

2018-06-21

Uncaria rhynchophylla, known as "Gou-teng", is a traditional Chinese medicine (TCM) used to extinguish wind, clear heat, arrest convulsions, and pacify the liver. Although U. rhynchophylla has a long history of being often used to treat central nervous system (CNS) diseases, its efficacy and potential mechanism are still uncertain. This study investigated neuroprotective effect and the underlying mechanism of U. rhynchophylla extract (URE) in MPP+-induced SH-SY5Y cells and MPTP-induced mice. MPP+-induced SH-SY5Y cells and MPTP-induced mice were used to established Parkinson's disease (PD) models. Quantitative proteomics and bioinformatics were used to uncover proteomics changes of URE. Western blotting was used to validate main differentially expressed proteins and test HSP90 client proteins (apoptosis-related, autophagy-related, MAPKs, PI3K, and AKT proteins). Flow cytometry and JC-1 staining assay were further used to confirm the effect of URE on MPP+-induced apoptosis in SH-SY5Y cells. Gait analysis was used to detect the behavioral changes in MPTP-induced mice. The levels of dopamine (DA) and their metabolites were examined in striatum (STR) by HPLC-EC. The positive expression of tyrosine hydroxylase (TH) was detected by immunohischemical staining and Western blotting. URE dose-dependently increased the cell viability in MPP+-induced SH-SY5Y cells. Quantitative proteomics and bioinformatics results confirmed that HSP90 was an important differentially expressed protein of URE. URE inhibited the expression of HSP90, which further reversed MPP+-induced cell apoptosis and autophagy by increasing the expressions of Bcl-2, Cyclin D1, p-ERK, p-PI3K p85, PI3K p110α, p-AKT, and LC3-I and decreasing cleaved caspase 3, Bax, p-JNK, p-p38, and LC3-II. URE also markedly decreased the apoptotic ratio and elevated mitochondrial transmembrane potential (DΨm). Furthermore, URE treatment ameliorated behavioral impairments, increased the contents of DA and its metabolites and

Structured DAG oil ameliorates renal injury in streptozotocin-induced diabetic rats through inhibition of NF-κB and activation of Nrf2 pathway.

PubMed

Das, Kankana; Ghosh, Mahua

2017-02-01

Accumulating evidence suggested that inflammatory processes are involved in the development of diabetic nephropathy (DN). Here, we have tested the hypothesis that Caprylic Acid (Cy)-diacylglycerol (DAG) oil (Cy-DAG), a novel structurally formulated lipid with high nutritional value, ameliorated DN in streptozotocin (STZ)-induced diabetic rats through the anti-inflammatory mechanisms. Basic hematological, biochemical parameters, immunoblotting, immunofluorescence and flow cytometry analysis were performed to observe the anti-inflammatory potential of Cy-DAG oil. The data revealed that STZ significantly increased the renal oxidative stress markers and decreased the levels of renal enzymatic and non-enzymatic antioxidants. Moreover, renal nitric oxide (NO), tissue necrosis factor-α (TNF-α), interleukin-6 (IL-6) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) were also increased in the renal tissue of STZ-treated rats. Further, DAG oil pretreatment produced a significant improvement in renal antioxidant status, reduced the lipid peroxidation and the levels of inflammatory markers in STZ-treated kidney. Similarly, results of protein expression showed that DAG oil pretreatment normalized the renal expression of Nrf2/Keap1 and its downstream regulatory proteins in STZ-treated condition. Immunohistochemical observations provided further evidence that DAG oil effectively protected the kidney from STZ-mediated oxidative damage. These results suggested that the DAG oil ameliorated STZ-induced oxidative renal injury by the activation of AKT/Nrf2/HO-1 pathway and the inhibition of ROS/MAPK/NF-κB pathway. Copyright © 2016 Elsevier Ltd. All rights reserved.

The 17,18-epoxyeicosatetraenoic acid-G protein-coupled receptor 40 axis ameliorates contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques.

PubMed

Nagatake, Takahiro; Shiogama, Yumiko; Inoue, Asuka; Kikuta, Junichi; Honda, Tetsuya; Tiwari, Prabha; Kishi, Takayuki; Yanagisawa, Atsushi; Isobe, Yosuke; Matsumoto, Naomi; Shimojou, Michiko; Morimoto, Sakiko; Suzuki, Hidehiko; Hirata, So-Ichiro; Steneberg, Pär; Edlund, Helena; Aoki, Junken; Arita, Makoto; Kiyono, Hiroshi; Yasutomi, Yasuhiro; Ishii, Masaru; Kabashima, Kenji; Kunisawa, Jun

2017-12-27

Metabolites of eicosapentaenoic acid exert various physiologic actions. 17,18-Epoxyeicosatetraenoic acid (17,18-EpETE) is a recently identified new class of antiallergic and anti-inflammatory lipid metabolite of eicosapentaenoic acid, but its effects on skin inflammation and the underlying mechanisms remain to be investigated. We evaluated the effectiveness of 17,18-EpETE for control of contact hypersensitivity in mice and cynomolgus macaques. We further sought to reveal underlying mechanisms by identifying the responsible receptor and cellular target of 17,18-EpETE. Contact hypersensitivity was induced by topical application of 2,4-dinitrofluorobenzene. Skin inflammation and immune cell populations were analyzed by using flow cytometric, immunohistologic, and quantitative RT-PCR analyses. Neutrophil mobility was examined by means of imaging analysis in vivo and neutrophil culture in vitro. The receptor for 17,18-EpETE was identified by using the TGF-α shedding assay, and the receptor's involvement in the anti-inflammatory effects of 17,18-EpETE was examined by using KO mice and specific inhibitor treatment. We found that preventive or therapeutic treatment with 17,18-EpETE ameliorated contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques. 17,18-EpETE was recognized by G protein-coupled receptor (GPR) 40 (also known as free fatty acid receptor 1) and inhibited chemoattractant-induced Rac activation and pseudopod formation in neutrophils. Indeed, the antiallergic inflammatory effect of 17,18-EpETE was abolished in the absence or inhibition of GPR40. 17,18-EpETE inhibits neutrophil mobility through GPR40 activation, which is a potential therapeutic target to control allergic inflammatory diseases. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Electroacupuncture ameliorates cognitive impairment through inhibition of NF-κB-mediated neuronal cell apoptosis in cerebral ischemia-reperfusion injured rats.

PubMed

Feng, Xiaodong; Yang, Shanli; Liu, Jiao; Huang, Jia; Peng, Jun; Lin, Jiumao; Tao, Jing; Chen, Lidian

2013-05-01

Cognitive impairment is a serious mental deficit following stroke that severely affects the quality of life of stroke survivors. Nuclear factor‑κB (NF-κB)-mediated neuronal cell apoptosis is involved in the development of post-stroke cognitive impairment; therefore, it has become a promising target for the treatment of impaired cognition. Acupuncture at the Baihui (DU20) and Shenting (DU24) acupoints is commonly used in China to clinically treat post‑stroke cognitive impairment; however, the precise mechanism of its action is largely unknown. In the present study, we evaluated the therapeutic efficacy of electroacupuncture against post-stroke cognitive impairment and investigated the underlying molecular mechanisms using a rat model of focal cerebral ischemia-reperfusion (I/R) injury. Electroacupuncture at Baihui and Shenting was identified to significantly ameliorate neurological deficits and reduce cerebral infarct volume. Additionally, electroacupuncture improved learning and memory ability in cerebral I/R injured rats, demonstrating its therapeutic efficacy against post-stroke cognitive impairment. Furthermore, electroacupuncture significantly suppressed the I/R-induced activation of NF-κB signaling in ischemic cerebral tissues. The inhibitory effect of electroacupuncture on NF-κB activation led to the inhibition of cerebral cell apoptosis. Finally, electroacupuncture markedly downregulated the expression of pro-apoptotic Bax and Fas, two critical downstream target genes of the NF-κB pathway. Collectively, our findings suggest that inhibition of NF-κB‑mediated neuronal cell apoptosis may be one mechanism via which electroacupuncture at Baihui and Shenting exerts a therapeutic effect on post-stroke cognitive impairment.

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.

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

EPA Science Inventory

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

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. © Georg Thieme Verlag KG Stuttgart · New York.

Proanthocyanidins from the bark of Metasequoia glyptostroboides ameliorate allergic contact dermatitis through directly inhibiting T cells activation and Th1/Th17 responses.

PubMed

Chen, Fengyang; Ye, Xiaodi; Yang, Yadong; Teng, Tianli; Li, Xiaoyu; Xu, Shifang; Ye, Yiping

2015-04-15

The leaves and bark of Metasequoia glyptostroboides are used as anti-microbic, analgesic and anti-inflammatory drug for dermatic diseases in Chinese folk medicine. However, the pharmacological effects and material basis responsible for the therapeutic use of this herb have not yet been well studied. The objectives of this study were to evaluate the anti-inflammatory effects of the proanthocyanidin fraction from the bark of M. glyptostroboides (MGEB) and to elucidate its immunological mechanisms. The anti-inflammatory activity of MGEB was evaluated using 2,4-dinitrofluorobenzene (DNFB)-induced allergic contact dermatitis (ACD) in mice. Its potential mechanisms were further investigated by determining its effects on Con A-induced T cell activation and Th1/Th17 responses in vitro. Both intraperitoneal injection and oral administration of MGEB significantly reduced the ear swelling in DNFB-induced ACD mice. MGEB inhibited Con A-induced proliferation and the expression levels of cell surface molecules CD69 and CD25 of T cells in vitro. MGEB also significantly decreased the production of Th1/Th17 specific cytokines (IL-2, IFN-γ and IL-17) and down-regulated their mRNA expression levels in activated T-cells. MGEB could ameliorate ACD, at least in part, through directly inhibiting T cells activation and Th1/Th17 responses. Copyright © 2015 Elsevier GmbH. All rights reserved.

Hemistepsin A ameliorates acute inflammation in macrophages via inhibition of nuclear factor-κB and activation of nuclear factor erythroid 2-related factor 2.

PubMed

Kim, Jae Kwang; Lee, Ji Eun; Jung, Eun Hye; Jung, Ji Yun; Jung, Dae Hwa; Ku, Sae Kwang; Cho, Il Je; Kim, Sang Chan

2018-01-01

Hemistepsin A (HsA) is a sesquiterpene lactone isolated from Hemistepta lyrata (Bunge) Bunge. We investigated the anti-inflammatory effects of HsA and sought to determine its mechanisms of action in macrophages. HsA pretreatment inhibited nitric oxide production, and reduced the expression of iNOS and COX-2 in Toll-like receptor ligand-stimulated RAW 264.7 cells. Additionally, HsA decreased the secretion of proinflammatory cytokines in lipopolysaccharide (LPS)-stimulated Kupffer cells as well as in RAW 264.7 cells. HsA inhibited phosphorylation of IKKα/β and degradation of IκBα, resulting in decreased nuclear translocation of nuclear factor-κB (NF-κB) and its transcriptional activity. Moreover, HsA phosphorylated nuclear factor erythroid 2-related factor 2 (Nrf2), increased expression levels of antioxidant genes, and attenuated LPS-stimulated H 2 O 2 production. Phosphorylation of p38 and c-Jun N-terminal kinase was required for HsA-mediated Nrf2 phosphorylation. In a D-galactosamine/LPS-induced liver injury model, HsA ameliorated D-galactosamine/LPS-induced hepatocyte degeneration and inflammatory cells infiltration. Moreover, immunohistochemical analyses using nitrotyrosine, 4-hydroxynonenal, and cleaved poly (ADP-ribose) polymerase antibodies revealed that HsA protected the liver from oxidative stress. Furthermore, HsA reduced the numbers of proinflammatory cytokine-positive cells in hepatic tissues. Thus, these results suggest HsA may be a promising natural product to manage inflammation-mediated tissue injuries through inhibition of NF-κB and activation of Nrf2. Copyright © 2017 Elsevier Ltd. All rights reserved.

Nonselective inhibition of prostaglandin-endoperoxide synthase by naproxen ameliorates hepatic injury in animals with acute or chronic liver injury

PubMed Central

Bahde, Ralf; Kapoor, Sorabh; Gupta, Sanjeev

2014-01-01

The rising prevalence of hepatic injury due to toxins, metabolites, viruses, etc., necessitates development of further mechanisms for protecting the liver and for treating acute or chronic liver diseases. To examine whether inhibition of inflammation directed by cyclo-oxygenase pathways, we performed animal studies with naproxen, which inhibits prostaglandin-endoperoxide synthases 1 and 2 and is in extensive clinical use. We administered carbon tetrachloride to induce acute liver injury and ligated the common bile duct to induce chronic liver injury in adult rats. These experimental manipulations produced abnormalities in liver tests, tissue necrosis, compensatory hepatocyte or biliary proliferation, and onset of fibrosis, particularly after bile duct ligation. After carbon tetrachloride-induced acute injury, naproxen decreased liver test abnormalities, tissue necrosis and compensatory hepatocellular proliferation. After bile duct ligation-induced chronic injury, naproxen decreased liver test abnormalities, tissue injury and compensatory biliary hyperplasia. Moreover, after bile duct ligation, naproxen-treated rats showed more periductular oval liver cells, which have been classified as hepatic progenitor cells. In naproxen-treated rats, we found greater expression in hepatic stellate cells and mononuclear cells of cytoprotective factors, such as vascular endothelial growth factor. The ability of naproxen to induce expression of vascular endothelial growth factor was verified in cell culture studies with CFSC-8B clone of rat hepatic stellate cells. Whereas assays for carbon tetrachloride toxicity using cultured primary hepatocytes established that naproxen was not directly cytoprotective, we found conditioned medium containing vascular endothelial growth factor from naproxen-treated CFSC-8B cells protected hepatocytes from carbon tetrachloride toxicity. Therefore, naproxen was capable of ameliorating toxic liver injury, which involved naproxen-induced release of

Galectin-9 ameliorates anti-GBM glomerulonephritis by inhibiting Th1 and Th17 immune responses in mice.

PubMed

Zhang, Qian; Luan, Hong; Wang, Le; He, Fan; Zhou, Huan; Xu, Xiaoli; Li, Xingai; Xu, Qing; Niki, Toshiro; Hirashima, Mitsuomi; Xu, Gang; Lv, Yongman; Yuan, Jin

2014-04-15

Antiglomerular basement membrane glomerulonephritis (anti-GBM GN) is a Th1- and Th17-predominant autoimmune disease. Galectin-9 (Gal-9), identified as the ligand of Tim-3, functions in diverse biological processes and leads to the apoptosis of CD4(+)Tim-3(+) T cells. It is still unclear how Gal-9 regulates the functions of Th1 and Th17 cells and prevents renal injury in anti-GBM GN. In this study, Gal-9 was administered to anti-GBM GN mice for 7 days. We found that Gal-9 retarded the increase of Scr, ameliorated renal tubular injury, and reduced the formation of crescents. The infiltration of Th1 and Th17 cells into the spleen and kidneys significantly decreased in Gal-9-treated nephritic mice. The reduced infiltration of Th1 and Th17 cells might be associated with the downregulation of CCL-20, CXCL-9, and CXCL-10 mRNAs in the kidney. In parallel, the blood levels of IFN-γ and IL-17A declined in Gal-9-treated nephritic mice at days 21 and 28. In addition, an enhanced Th2 cell-mediated immune response was observed in the kidneys of nephritic mice after a 7-day injection of Gal-9. In conclusion, the protective role of Gal-9 in anti-GBM GN is associated with the inhibition of Th1 and Th17 cell-mediated immune responses and enhanced Th2 immunity in the kidney.

Interleukin-22 ameliorates liver fibrosis through miR-200a/beta-catenin

PubMed Central

Hu, Bang-li; Shi, Cheng; Lei, Rong-e; Lu, Dong-hong; Luo, Wei; Qin, Shan-yu; Zhou, You; Jiang, Hai-xing

2016-01-01

IL-22 ameliorates liver fibrosis by inhibiting hepatic stellate cells (HSC), and loss of miR-200a is associated with the development of liver fibrosis. The study aimed to investigate the interplay between IL-22 and miR-200a in regulating liver fibrosis in vivo and in vitro. We observed that IL-22 significantly reduced the proliferation of HSC and increased the expression of p-STAT3. β-catenin was identified as a target gene of miR-200a by luciferase reporter assay, and upregulation of miR-200a significantly attenuated the proliferation of HSC and reduced β-catenin expression. IL-22 treatment increased expression of miR-200a and decreased expression of β-catenin in HSC. The expression of p-STAT3 and miR-200a was elevated while β-catenin was decreased in fibrotic rat liver after IL-22 treatment. Expression levels of β-catenin and p-STAT3 were inversely correlated in fibrotic rat liver and HSC. Upregulation of β-catenin suppressed expression of p-STAT3 in HSC. We concluded that IL-22 inhibits HSC activation and ameliorates liver fibrosis through enhancing expression of miR-200a and reducing expression of β-catenin, suggesting there may be a crosstalk between IL-22/STAT3 and β-catenin pathway. PMID:27819314

Amelioration of radiation-induced hematopoietic and gastrointestinal damage by Ex-RAD® in mice

PubMed Central

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

2012-01-01

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. PMID:22843617

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. © Georg Thieme Verlag KG Stuttgart · New York.

ShaoYao decoction ameliorates colitis-associated colorectal cancer by downregulating proinflammatory cytokines and promoting epithelial-mesenchymal transition

PubMed Central

2014-01-01

Abstracts Background Shaoyao decoction (SYD) is a traditional Chinese medicine prescription formulated by Liu Wan-Su, a master of traditional Chinese medicine in Jin-Yuan Dynasty. SYD is effective in treating ulcerative colitis. Paeonol, a component of SYD, inhibits colorectal cancer (CRC) cell proliferation and induces CRC cell apoptosis. In this study, azoxymethane (AOM)/dextran sodium sulfate (DSS)–induced colitis-associated CRC (caCRC) model and CRC cell lines were used to examine the effects of SYD on CRC in vivo and in vitro. Methods A translational medicine strategy based on phytomics quality control was adopted. Liquid chromatography was employed for the chemical characterization and chemical fingerprinting of SYD. Protein expression and macrophage existence were determined by immunohistochemistry and western blot. Serum cytokines were quantified by Luminex assay. Results AOM/DSS-induced caCRC phenotypically resembled human caCRC. SYD significantly increased the survival rate of the mice, ameliorated the general well-being of the mice, and reduced the incidence and multiplicity of colonic neoplasms. SYD inhibited epithelial–mesenchymal transition (EMT), as indicated by upregulated epithelia cadherin and downregulated neuronal cadherin, fibronectin, vimentin, and transcription factor Snail. SYD reduced the expression levels of serum interleukin 1β, interleukin-6, tumor necrosis factor α, tumor-associated macrophages, and p65. These results showed that SYD can attenuate proinflammatory cytokines and inhibit EMT. Conclusions SYD ameliorates caCRC by suppressing inflammation and inhibiting EMT. SYD might be an alternative therapy for caCRC. PMID:24766737

The memory-ameliorating effects of Artemisia princeps var. orientalis against cholinergic dysfunction in mice.

PubMed

Liu, Xiaotong; Kim, Dong Hyun; Kim, Jong Min; Park, Se Jin; Cai, Mudan; Jang, Dae Sik; Ryu, Jong Hoon

2012-01-01

Artemisia princeps var. orientalis (Compositae) is widely distributed in China, Japan and Korea and is known to have anti-inflammatory and anti-oxidative activities. The ethyl acetate fraction of ethanolic extract of A. princeps var. orientalis (AEA) was found to inhibit acetylcholinesterase activity in a dose-dependent manner in vitro (IC(50) value: 541.4 ± 67.5 μg/ml). Therefore, we investigated the effects of AEA on scopolamine-induced learning and memory impairment using the passive avoidance, the Y-maze, and the Morris water maze tasks in mice. AEA (100 or 200 mg/kg, p.o.) significantly ameliorated scopolamine-induced cognitive impairments in the passive avoidance and Y-maze tasks (p < 0.05). In the Morris water maze task, AEA (200 mg/kg, p.o.) significantly shortened escape latencies in training trials and increased both swimming time spent in the target zone and probe crossing numbers during the probe trial as compared with scopolamine-treated mice (p < 0.05). Additionally, the ameliorating effect of AEA on scopolamine-induced memory impairment was antagonized by a subeffective dose of MK-801. These results suggest that AEA could be an effective treatment against cholinergic dysfunction and its effect is mediated by the enhancement of the cholinergic neurotransmitter system via NMDA receptor signaling or acetylcholinesterase inhibition.

PAMs ameliorates the imiquimod-induced psoriasis-like skin disease in mice by inhibition of translocation of NF-κB and production of inflammatory cytokines.

PubMed

Dou, Rongkun; Liu, Zongying; Yuan, Xue; Xiangfei, Danzhou; Bai, Ruixue; Bi, Zhenfei; Yang, Piao; Yang, Yalan; Dong, Yinsong; Su, Wei; Li, Diqiang; Mao, Canquan

2017-01-01

Psoriasis is a chronic and persistent inflammatory skin disease seriously affecting the quality of human life. In this study, we reported an ancient formula of Chinese folk medicine, the natural plant antimicrobial solution (PAMs) for its anti-inflammatory effects and proposed the primary mechanisms on inhibiting the inflammatory response in TNF-α/IFN-γ-induced HaCaT cells and imiquimod-induced psoriasis-like skin disease mouse model. Two main functional components of hydroxysafflor Yellow A and allantoin in PAMs were quantified by HPLC to be 94.2±2.2 and 262.9±12.5 μg/mL respectively. PAMs could significantly reduce the gene expression and inflammatory cytokines production of Macrophage-Derived Chemokine (MDC), IL-8 and IL-6 in TNF-α/IFN-γ-induced HaCaT cells. PAMs also significantly ameliorates the psoriatic-like symptoms in a mouse model with the evaluation scores for both the single (scales, thickness, erythema) and cumulative features were in the order of blank control < Dexamethasone < PAMs < 50% ethanol < model groups. The results were further confirmed by hematoxylin-eosin staining, RT-qPCR and immunohistochemistry. The down-regulated gene expression of IL-8, TNF-α, ICAM-1 and IL-23 in mouse tissues was consistent with the results from those of the HaCaT cells. The inhibition of psoriasis-like skin inflammation by PAMs was correlated with the inactivation of the translocation of P65 protein into cellular nucleus, indicating the inhibition of the inflammatory NF-κB signaling pathway. Taken together, these findings suggest that PAMs may be a promising drug candidate for the treatment of inflammatory skin disorders, such as psoriasis.

Tyrosine kinase inhibition ameliorates the hyperdynamic state and decreases nitric oxide production in cirrhotic rats with portal hypertension and ascites.

PubMed Central

López-Talavera, J C; Levitzki, A; Martínez, M; Gazit, A; Esteban, R; Guardia, J

1997-01-01

Tumor necrosis factor-alpha (TNF) causes vasodilatation and a hyperdynamic state by activating nitric oxide (NO) synthesis. Tyrphostins, specific inhibitors of protein tyrosine kinase (PTK), block the signaling events induced by TNF and NO production. A hyperdynamic circulatory syndrome (HCS) is often observed in portal hypertension (PHT). TNF and NO seem to mediate these hemodynamic changes. The aim of this work was to study the effect of PTK inhibition on the systemic and portal hemodynamics, TNF and NO production, in cirrhotic rats with portal hypertension. Rats with liver cirrhosis induced by chronic inhalation of carbon tetrachloride were used. Animals were treated daily with tyrphostin AG 126 (alpha-cyano-(3-hydroxy-4-nitro) cinnamonitrile) or placebo for 5 d. Mean arterial pressure (MAP), heart rate (HR), and portal pressure (PP) were measured by indwelling catheters. Cardiac output (CI) and stroke volume (SV) were estimated by thermodilution, systemic vascular resistance (SVR) was calculated (MAP/CI), and portal systemic shunting (PSS) was quantitated using radioactive microspheres. Serum and mesenteric lymph node (MLN) TNF levels were measured using an immunoassay kit, and serum NOx was determined photometrically by its oxidation products. The AG 126-treated group showed a statistically significant increase in MAP and SVR, and decreases in CI, SV, MLN TNF, and serum NO oxidation products nitrite and nitrate (NOx) in comparison with the placebo-treated rats. No significant differences were noticed in HR, PP, PSS, or serum TNF. Significant correlations were observed between MAP and NOx, MAP and MLN TNF, PSS and NOx, and serum TNF and serum NOx. The HCS observed in PHT seems to be mediated, at least in part, by TNF and NO by the activation of PTKs and their signaling pathways. PTK activity inhibition ameliorates the hyperdynamic abnormalities that characterize animals with cirrhosis and PHT. PMID:9239414

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

Ameliorants to immobilize Cd in rice paddy soils contaminated by abandoned metal mines in Korea.

PubMed

Ok, Yong Sik; Kim, Sung-Chul; Kim, Dong-Kuk; Skousen, Jeffrey G; Lee, Jin-Soo; Cheong, Young-Wook; Kim, Su-Jung; Yang, Jae E

2011-01-01

The cadmium (Cd) content of rice grain grown in metal-contaminated paddy soils near abandoned metal mines in South Korea was found to exceed safety guidelines (0.2 mg Cd kg⁻¹) set by the Korea Food and Drug Administration (KFDA). However, current remediation technologies for heavy metal-contaminated soils have limited application with respect to rice paddy soils. Laboratory and greenhouse experiments were conducted to assess the effects of amending contaminated rice paddy soils with zerovalent iron (ZVI), lime, humus, compost, and combinations of these compounds to immobilize Cd and inhibit Cd translocation to rice grain. Sequential extraction analysis revealed that treatment with the ameliorants induced a 50-90% decrease in the bioavailable Cd fractions when compared to the untreated control soil. When compared to the control, Cd uptake by rice was decreased in response to treatment with ZVI + humus (69%), lime (65%), ZVI + compost (61%), compost (46%), ZVI (42%), and humus (14%). In addition, ameliorants did not influence rice yield when compared to that of the control. Overall, the results of this study indicated that remediation technologies using ameliorants effectively reduce Cd bioavailability and uptake in contaminated rice paddy soils.

Inhibition of GSK-3beta ameliorates hepatic ischemia-reperfusion injury through GSK-3beta/beta-catenin signaling pathway in mice.

PubMed

Xia, Yong-Xiang; Lu, Ling; Wu, Zheng-Shan; Pu, Li-Yong; Sun, Bei-Cheng; Wang, Xue-Hao

2012-06-01

Glycogen synthase kinase (GSK)-3beta/beta-catenin signaling regulates ischemia-reperfusion (I/R)-induced apoptosis and proliferation, and inhibition of GSK-3beta has beneficial effects on I/R injury in the heart and the central nervous system. However, the role of this signaling in hepatic I/R injury remains unclear. The present study aimed to investigate the effects and mechanism of GSK-3beta/beta-catenin signaling in hepatic I/R injury. Male C57BL/6 mice (weighing 22-25 g) were pretreated with either SB216763, an inhibitor of GSK-3beta, or vehicle. These mice were subjected to partial hepatic I/R. Blood was collected for test of alanine aminotransferase (ALT), and liver specimen for assays of phosphorylation at the Ser9 residue of GSK-3beta, GSK-3beta activity, axin 2 and the anti-apoptotic factors Bcl-2 and survivin, as well as the proliferative factors cyclin D1 and proliferating cell nuclear antigen, and apoptotic index (TUNEL). Real-time PCR, Western blotting and immunohistochemical staining were used. SB216763 increased phospho-GSK-3beta levels and suppressed GSK-3beta activity (1880+/-229 vs 3280+/-272 cpm, P<0.01). ALT peaked at 6 hours after reperfusion. Compared with control, SB216763 decreased ALT after 6 hours of reperfusion (4451+/-424 vs 7868+/-845 IU/L, P<0.01), and alleviated hepatocyte necrosis and vacuolization. GSK-3beta inhibition led to the accumulation of beta-catenin in the cytosol (0.40+/-0.05 vs 1.31+/-0.11, P<0.05) and nucleus (0.62+/-0.14 vs 1.73+/-0.12, P<0.05), beta-catenin further upregulated the expression of axin 2. Upregulation of GSK-3beta/beta-catenin signaling increased Bcl-2, survivin and cyclin D1. Serological and histological analyses showed that SB216763 alleviated hepatic I/R-induced injury by reducing apoptosis (1.4+/-0.2% vs 3.6+/-0.4%, P<0.05) and enhanced liver proliferation (56+/-8% vs 19+/-4%, P<0.05). Inhibition of GSK-3beta ameliorates hepatic I/R injury through the GSK-3beta/beta-catenin signaling pathway.

Human umbilical cord mesenchymal stem cells ameliorate mice trinitrobenzene sulfonic acid (TNBS)-induced colitis.

PubMed

Liang, Lu; Dong, Chunlan; Chen, Xiaojun; Fang, Zhihong; Xu, Jie; Liu, Meng; Zhang, Xiaoguang; Gu, Dong Sheng; Wang, Ding; Du, Weiting; Zhu, Delin; Han, Zhong Chao

2011-01-01

Mesenchymal stem cells (MSCs), which are poorly immunogenic and have potent immunosuppressive activities, have emerged as a promising candidate for cellular therapeutics for the treatment of disorders caused by abnormal immune responses. In this study we investigated whether human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) could ameliorate colitis in a trinitrobenzene sulfonic acid (TNBS)-induced colitis model. TNBS-treated colitic mice were infused with hUC-MSCs or vehicle control. The mice were sacrificed on day 1, 3, and 5 after infusion, and their clinical and pathological conditions were evaluated by body weight, colon length, and histological analysis. The expression levels of proinflammatory cytokine proteins in colon were examined by ELISA. The homing of hUC-MSCs was studied by live in vivo imaging and immunofluorescent microscopy. hUC-MSCs were found to migrate to the inflamed colon and effectively treated the colitic mice with improved clinical and pathological signs. The levels of IL-17 and IL-23 as well as IFN-γ and IL-6 were significantly lower in the colon tissues of the hUC-MSC-treated mice in comparison with the vehicle-treated mice. Coculture experiments showed that hUC-MSCs not only could inhibit IFN-γ expression but also significantly inhibit IL-17 production by lamina propria mononuclear cells (LPMCs) or splenocytes of the colitic mice or by those isolated from normal animals and stimulated with IL-23. Systemically infused hUC-MSCs could home to the inflamed colon and effectively ameliorate colitis. In addition to the known suppressive effects on Th1-type immune responses, hUC-MSC-mediated modulation of IL-23/IL-17 regulated inflammatory reactions also plays an important role in the amelioration of colitis.

Resveratrol Ameliorates Microcystin-LR-Induced Testis Germ Cell Apoptosis in Rats via SIRT1 Signaling Pathway Activation.

PubMed

Liu, Haohao; Zhang, Shenshen; Liu, Chuanrui; Wu, Jinxia; Wang, Yueqin; Yuan, Le; Du, Xingde; Wang, Rui; Marwa, Phelisters Wegesa; Zhuang, Donggang; Cheng, Xuemin; Zhang, Huizhen

2018-06-09

Microcystin-leucine arginine (MC-LR), a cyclic heptapeptide produced by cyanobacteria, is a strong reproductive toxin. Studies performed in rat Sertoli cells and Chinese hamster ovary cells have demonstrated typical apoptosis after MC-LR exposure. However, little is known on how to protect against the reproductive toxicity induced by MC-LR. The present study aimed to explore the possible molecular mechanism underlying the anti-apoptosis and protective effects of resveratrol (RES) on the co-culture of Sertoli⁻germ cells and rat testes. The results demonstrated that MC-LR treatment inhibited the proliferation of Sertoli⁻germ cells and induced apoptosis. Furthermore, sirtuin 1 (SIRT1) and Bcl-2 were inhibited, while p53 and Ku70 acetylation, Bax expression, and cleaved caspase-3 were upregulated by MC-LR. However, RES pretreatment ameliorated MC-LR-induced apoptosis and SIRT1 inhibition, and downregulated the MC-LR-induced increase in p53 and Ku70 acetylation, Bax expression, and caspase-3 activation. In addition, RES reversed the MC-LR-mediated reduction in Ku70 binding to Bax. The present study indicated that the administration of RES could ameliorate MC-LR-induced Sertoli⁻germ cell apoptosis and protect against reproductive toxicity in rats by stimulating the SIRT1/p53 pathway, suppressing p53 and Ku70 acetylation and enhancing the binding of Ku70 to Bax.

Mitochondrial division/mitophagy inhibitor (Mdivi) Ameliorates Pressure Overload Induced Heart Failure

PubMed Central

Givvimani, Srikanth; Munjal, Charu; Tyagi, Neetu; Sen, Utpal; Metreveli, Naira; Tyagi, Suresh C.

2012-01-01

Background We have previously reported the role of anti-angiogenic factors in inducing the transition from compensatory cardiac hypertrophy to heart failure and the significance of MMP-9 and TIMP-3 in promoting this process during pressure overload hemodynamic stress. Several studies reported the evidence of cardiac autophagy, involving removal of cellular organelles like mitochondria (mitophagy), peroxisomes etc., in the pathogenesis of heart failure. However, little is known regarding the therapeutic role of mitochondrial division inhibitor (Mdivi) in the pressure overload induced heart failure. We hypothesize that treatment with mitochondrial division inhibitor (Mdivi) inhibits abnormal mitophagy in a pressure overload heart and thus ameliorates heart failure condition. Materials and Methods To verify this, ascending aortic banding was done in wild type mice to create pressure overload induced heart failure and then treated with Mdivi and compared with vehicle treated controls. Results Expression of MMP-2, vascular endothelial growth factor, CD31, was increased, while expression of anti angiogenic factors like endostatin and angiostatin along with MMP-9, TIMP-3 was reduced in Mdivi treated AB 8 weeks mice compared to vehicle treated controls. Expression of mitophagy markers like LC3 and p62 was decreased in Mdivi treated mice compared to controls. Cardiac functional status assessed by echocardiography showed improvement and there is also a decrease in the deposition of fibrosis in Mdivi treated mice compared to controls. Conclusion Above results suggest that Mdivi inhibits the abnormal cardiac mitophagy response during sustained pressure overload stress and propose the novel therapeutic role of Mdivi in ameliorating heart failure. PMID:22479323

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.

Daikenchuto, a traditional Japanese herbal medicine, ameliorates postoperative ileus by anti-inflammatory action through nicotinic acetylcholine receptors.

PubMed

Endo, Mari; Hori, Masatoshi; Ozaki, Hiroshi; Oikawa, Tetsuro; Hanawa, Toshihiko

2014-06-01

Daikenchuto (DKT), a gastrointestinal prokinetic Japanese herbal medicine, is prescribed for patients with postoperative ileus (POI) and adhesive bowel obstruction following abdominal surgery. Several mechanisms for the amelioration of POI by DKT have been suggested; however, it has remained unclear whether DKT shows anti-inflammatory effects in POI. In the present study, we investigated the effects of DKT in a mouse POI model and attempted to clarify the detailed mechanisms of action. Intestinal manipulation (IM) was applied to the distal ileum of mice. DKT was administered orally to the animals 4 times before and after IM. Gastrointestinal transit in vivo, leukocyte infiltration, cytokine mRNA expression and gastrointestinal motility were analyzed. We also investigated the effects of the α7nAChR antagonist methyllycaconitine citrate (MLA) on the DKT-mediated ameliorative action against POI, and we studied the effects of DKT on inflammatory activity in α7nAChR knockout mice. DKT treatment led to recovery of the delayed intestinal transit induced by IM. DKT significantly inhibited the infiltration of neutrophils and CD68-positive macrophages, and inhibited mRNA expressions of TNF-α and MCP-1. MLA significantly reduced the anti-inflammatory action of DKT, and the amelioration of macrophage infiltration by DKT was partially suppressed in α7nAChR knockout mice. In conclusion, in addition to the gastrointestinal prokinetic action, DKT serves as a novel therapeutic agent for POI characterized by its anti-inflammatory potency. The DKT-induced anti-inflammatory activity may be partly mediated by activation of α7nAChR.

Vildagliptin ameliorates pulmonary fibrosis in lipopolysaccharide-induced lung injury by inhibiting endothelial-to-mesenchymal transition.

PubMed

Suzuki, Toshio; Tada, Yuji; Gladson, Santhi; Nishimura, Rintaro; Shimomura, Iwao; Karasawa, Satoshi; Tatsumi, Koichiro; West, James

2017-10-16

cells or GLP-1. Inhibiting DPP-4 signaling by vildagliptin could ameliorate pulmonary fibrosis by downregulating EndMT in systemic LPS-induced lung injury.

Plasmodium berghei infection ameliorates atopic dermatitis-like skin lesions in NC/Nga mice.

PubMed

Kishi, C; Amano, H; Suzue, K; Ishikawa, O

2014-10-01

Atopic diseases are more prevalent in industrialized countries than in developing countries. In addition, significant differences in the prevalence of allergic diseases are observed between rural and urban areas within the same country. This difference in prevalence has been attributed to what is called the 'hygiene hypothesis'. Although parasitic infections are known to protect against allergic reactions, the mechanism is still unknown. The aim of this study was to investigate whether or not malarial infections can inhibit atopic dermatitis (AD)-like skin lesions in a mouse model of AD. We used NC/Nga mice which are a model for AD. The NC/Nga mice were intraperitoneally infected with 1 × 10(5) Plasmoduim berghei (Pb) XAT-infected erythrocytes. Malarial infections ameliorated AD-like skin lesions in the NC/Nga mice. This improvement was blocked by the administration of anti-asialo GM1 antibodies, which are anti-natural killer (NK) cells. Additionally, adoptive transfer of NK cells markedly improved AD-like skin lesions in conventional NC/Nga mice; these suggest that the novel protective mechanism associated with malaria parasitic infections is at least, in part, dependent on NK cells. We have experimentally demonstrated for the first time that malarial infections ameliorated AD-like skin lesions in a mouse model of AD. Our study could explain in part the mechanism of the 'hygiene hypothesis', which states that parasitic infections can inhibit the development of allergic diseases. © 2014 The Authors. Allergy Published by John Wiley & Sons Ltd.

Ferulic acid ameliorates memory impairment in d-galactose-induced aging mouse model.

PubMed

Yang, Honggai; Qu, Zhuo; Zhang, Jingze; Huo, Liqin; Gao, Jing; Gao, Wenyuan

2016-11-01

Ferulic acid (FA) acts as a powerful antioxidant against various age-related diseases. To investigate the effect and underlying mechanism of FA against d-galactose(d-gal)-induced memory deficit, mice were injected with d-gal to induce memory impairment and simultaneously treated with FA and donepezil. The behavioral results revealed that chronic FA treatment reversed d-gal-induced memory impairment. Further, FA treatment inhibited d-gal-induced AChE activity and oxidative stress via increase of superoxide dismutase activity and reduced glutathione content, as well as decrease of malondialdehyde and nitric oxide levels. We also observed that FA significantly inhibits inflammation in the brain through reduction of NF-κB and IL-1β by enzyme-linked immunosorbent assay. Additionally, FA treatment significantly reduces the caspase-3 level in the hippocampus of d-gal-treated mice. Hematoxylin and eosin and Nissl staining showed that FA prevents neurodegeneration induced by d-gal. These findings showed that FA inhibits d-gal-induced AChE activity, oxidative stress, neuroinflammation and neurodegeneration, and consequently ameliorates memory impairment.

Erhuang Formula ameliorates renal damage in adenine-induced chronic renal failure rats via inhibiting inflammatory and fibrotic responses.

PubMed

Zhang, Chun-Yan; Zhu, Jian-Yong; Ye, Ying; Zhang, Miao; Zhang, Li-Jun; Wang, Su-Juan; Song, Ya-Nan; Zhang, Hong

2017-11-01

The present study aimed to evaluate the protective effects of Erhuang Formula (EHF) and explore its pharmacological mechanisms on adenine-induced chronic renal failure (CRF). The compounds in EHF were analyzed by HPLC/MS. Adenine-induced CRF rats were administrated by EHF. The effects were evaluated by renal function examination and histology staining. Immunostaining of some proteins related cell adhesion was performedin renal tissues, including E-cadherin, β-catenin, fibronectin and laminin. The qRT-PCR was carried out determination of gene expression related inflammation and fibrosis including NF-κB, TNF-α, TGF-β1, α-SMA and osteopontin (OPN). Ten compounds in EHF were identified including liquiritigenin, farnesene, vaccarin, pachymic acid, cycloastragenol, astilbin, 3,5,6,7,8,3',4'-heptemthoxyflavone, physcion, emodin and curzerene. Abnormal renal function and histology had significant improvements by EHF treatment. The protein expression of β-catenin, fibronectin and laminin were significantly increased and the protein expression of E-cadherin significantly decreased in CRF groups. However, these protein expressions were restored to normal levels in EHF group. Furthermore, low expression of PPARγ and high expression of NF-κB, TNF-α, TGF-β1, α-SMA and OPN were substantially restored by EHF treatment in a dose-dependent manner. EHF ameliorated renal damage in adenine-induced CRF rats, and the mechanisms might involve in the inhibition of inflammatory and fibrotic responses and the regulation of PPARγ, NF-κB and TGF-β signaling pathways. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Bergenin, Acting as an Agonist of PPARγ, Ameliorates Experimental Colitis in Mice through Improving Expression of SIRT1, and Therefore Inhibiting NF-κB-Mediated Macrophage Activation.

PubMed

Wang, Kai; Li, Yun-Fan; Lv, Qi; Li, Xi-Ming; Dai, Yue; Wei, Zhi-Feng

2017-01-01

Bergenin, isolated from the herb of Saxifraga stolonifera Curt. (Hu-Er-Cao), has anti-inflammatory, antitussive and wound healing activities. The aim of the present study was to identify the effect of bergenin on experimental colitis, and explored the related mechanisms. Our results showed that oral administration of bergenin remarkably alleviated disease symptoms of mice with dextran sulfate sodium (DSS)-induced colitis, evidenced by reduced DAI scores, shortening of colon length, MPO activity and pathologic abnormalities in colons. Bergenin obviously inhibited the mRNA and protein expressions of IL-6 and TNF-α in colon tissues, but not that of mucosal barrier-associated proteins occludin, E -cadherin and MUC-2. In vitro , bergenin significantly inhibited the expressions of IL-6 and TNF-α as well as nuclear translocation and DNA binding activity of NF-κB-p65 in lipopolysaccharide (LPS)-stimulated peritoneal macrophages and RAW264.7 cells, which was almost reversed by addition of PPARγ antagonist GW9662 and siPPARγ. Subsequently, bergenin was identified as a PPARγ agonist. It could enter into macrophages, bind with PPARγ, promote nuclear translocation and transcriptional activity of PPARγ, and increase mRNA expressions of CD36, LPL and ap2. In addition, bergenin significantly up-regulated expression of SIRT1, inhibited acetylation of NF-κB-p65 and increased association NF-κB-p65 and IκBα. Finally, the correlation between activation of PPARγ and attenuation of colitis, inhibition of IL-6 and TNF-α expressions, NF-κB-p65 acetylation and nuclear translocation, and up-regulation of SIRT1 expression by bergenin was validated in mice with DSS-induced colitis and/or LPS-stimulated macrophages. In summary, bergenin could ameliorate colitis in mice through inhibiting the activation of macrophages via regulating PPARγ/SIRT1/NF-κB-p65 pathway. The findings can provide evidence for the further development of bergenin as an anti-UC drug, and offer a paradigm

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.

Reinforcement and stimulant medication ameliorate deficient response inhibition in children with Attention-Deficit/Hyperactivity Disorder

PubMed Central

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

2015-01-01

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

Dammarane Sapogenins Ameliorates Neurocognitive Functional Impairment Induced by Simulated Long-Duration Spaceflight.

PubMed

Wu, Xiaorui; Li, Dong; Liu, Junlian; Diao, Lihong; Ling, Shukuan; Li, Yuheng; Gao, Jianyi; Fan, Quanchun; Sun, Weijia; Li, Qi; Zhao, Dingsheng; Zhong, Guohui; Cao, Dengchao; Liu, Min; Wang, Jiaping; Zhao, Shuang; Liu, Yu; Bai, Guie; Shi, Hongzhi; Xu, Zi; Wang, Jing; Xue, Chunmei; Jin, Xiaoyan; Yuan, Xinxin; Li, Hongxing; Liu, Caizhi; Sun, Huiyuan; Li, Jianwei; Li, Yongzhi; Li, Yingxian

2017-01-01

Increasing evidence indicates the occurrence of cognitive impairment in astronauts under spaceflight compound conditions, but the underlying mechanisms and countermeasures need to be explored. In this study, we found that learning and memory abilities were significantly reduced in rats under a simulated long-duration spaceflight environment (SLSE), which includes microgravity, isolation confinement, noises, and altered circadian rhythms. Dammarane sapogenins (DS), alkaline hydrolyzed products of ginsenosides, can enhance cognition function by regulating brain neurotransmitter levels and inhibiting SLSE-induced neuronal injury. Bioinformatics combined with experimental verification identified that the PI3K-Akt-mTOR pathway was inhibited and the MAPK pathway was activated during SLSE-induced cognition dysfunction, whereas DS substantially ameliorated the changes in brain. These findings defined the characteristics of SLSE-induced cognitive decline and the mechanisms by which DS improves it. The results provide an effective candidate for improving cognitive function in spaceflight missions.

Dammarane Sapogenins Ameliorates Neurocognitive Functional Impairment Induced by Simulated Long-Duration Spaceflight

PubMed Central

Wu, Xiaorui; Li, Dong; Liu, Junlian; Diao, Lihong; Ling, Shukuan; Li, Yuheng; Gao, Jianyi; Fan, Quanchun; Sun, Weijia; Li, Qi; Zhao, Dingsheng; Zhong, Guohui; Cao, Dengchao; Liu, Min; Wang, Jiaping; Zhao, Shuang; Liu, Yu; Bai, Guie; Shi, Hongzhi; Xu, Zi; Wang, Jing; Xue, Chunmei; Jin, Xiaoyan; Yuan, Xinxin; Li, Hongxing; Liu, Caizhi; Sun, Huiyuan; Li, Jianwei; Li, Yongzhi; Li, Yingxian

2017-01-01

Increasing evidence indicates the occurrence of cognitive impairment in astronauts under spaceflight compound conditions, but the underlying mechanisms and countermeasures need to be explored. In this study, we found that learning and memory abilities were significantly reduced in rats under a simulated long-duration spaceflight environment (SLSE), which includes microgravity, isolation confinement, noises, and altered circadian rhythms. Dammarane sapogenins (DS), alkaline hydrolyzed products of ginsenosides, can enhance cognition function by regulating brain neurotransmitter levels and inhibiting SLSE-induced neuronal injury. Bioinformatics combined with experimental verification identified that the PI3K-Akt-mTOR pathway was inhibited and the MAPK pathway was activated during SLSE-induced cognition dysfunction, whereas DS substantially ameliorated the changes in brain. These findings defined the characteristics of SLSE-induced cognitive decline and the mechanisms by which DS improves it. The results provide an effective candidate for improving cognitive function in spaceflight missions. PMID:28611667

Neuroprotective Effects of Protein Tyrosine Phosphatase 1B Inhibition against ER Stress-Induced Toxicity

PubMed Central

Jeon, Yu-Mi; Lee, Shinrye; Kim, Seyeon; Kwon, Younghwi; Kim, Kiyoung; Chung, Chang Geon; Lee, Seongsoo; Lee, Sung Bae; Kim, Hyung-Jun

2017-01-01

Several lines of evidence suggest that endoplasmic reticulum (ER) stress plays a critical role in the pathogenesis of many neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Protein tyrosine phosphatase 1B (PTP1B) is known to regulate the ER stress signaling pathway, but its role in neuronal systems in terms of ER stress remains largely unknown. Here, we showed that rotenone-induced toxicity in human neuroblastoma cell lines and mouse primary cortical neurons was ameliorated by PTP1B inhibition. Moreover, the increase in the level of ER stress markers (eIF2α phosphorylation and PERK phosphorylation) induced by rotenone treatment was obviously suppressed by concomitant PTP1B inhibition. However, the rotenone-induced production of reactive oxygen species (ROS) was not affected by PTP1B inhibition, suggesting that the neuroprotective effect of the PTP1B inhibitor is not associated with ROS production. Moreover, we found that MG132-induced toxicity involving proteasome inhibition was also ameliorated by PTP1B inhibition in a human neuroblastoma cell line and mouse primary cortical neurons. Consistently, downregulation of the PTP1B homologue gene in Drosophila mitigated rotenone- and MG132-induced toxicity. Taken together, these findings indicate that PTP1B inhibition may represent a novel therapeutic approach for ER stress-mediated neurodegenerative diseases. PMID:28359145

Osthole ameliorates hepatic fibrosis and inhibits hepatic stellate cell activation.

PubMed

Liu, Ya-Wei; Chiu, Yung-Tsung; Fu, Shu-Ling; Huang, Yi-Tsau

2015-08-01

Hepatic fibrosis is a dynamic process which ultimately leads to cirrhosis in almost patients with chronic hepatic injury. However, progressive fibrosis is a reversible scarring response. Activation of hepatic stellate cells (HSCs) is the prevailing process during hepatic fibrosis. Osthole is an active component majorly contained in the fruit of Cnidium monnieri (L.) Cusson. This present study investigated the therapeutic effects of osthole on rat liver fibrosis and HSC activation. We established the thioacetamide (TAA)-model of Sprague-Dawley (SD) rats to induce hepatic fibrosis. Rats were divided into three groups: control, TAA, and TAA + osthole (10 mg/kg). In vivo, osthole significantly reduced liver injury by diminishing levels of plasma AST and ALT, improving histological architecture, decreasing collagen and α-SMA accumulation, and improving hepatic fibrosis scores. Additionally, osthole reduced the expression of fibrosis-related genes significantly. Osthole also suppressed the production of fibrosis-related cytokines and chemokines. Moreover, nuclear translocation of p65 was significantly suppressed in osthole-treated liver. Osthole also ameliorated TAA-induced injury through reducing cellular oxidation. Osthole showed inhibitory effects in inflammation-related genes and chemokines production as well. In vitro, we assessed osthole effects in activated HSCs (HSC-T6 and LX-2). Osthole attenuated TGF-β1-induced migration and invasion in HSCs. Furthermore, osthole decreased TNF-α-triggered NF-κB activities significantly. Besides, osthole alleviated TGF-β1- or ET-1-induced HSCs contractility. Our study demonstrated that osthole improved TAA-caused liver injury, fibrogenesis and inflammation in rats. In addition, osthole suppressed HSCs activation in vitro significantly.

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. Copyright © 2014 Elsevier B.V. All rights reserved.

Serine racemase is associated with schizophrenia susceptibility in humans and in a mouse model

PubMed Central

Labrie, Viviane; Fukumura, Ryutaro; Rastogi, Anjali; Fick, Laura J.; Wang, Wei; Boutros, Paul C.; Kennedy, James L.; Semeralul, Mawahib O.; Lee, Frankie H.; Baker, Glen B.; Belsham, Denise D.; Barger, Steven W.; Gondo, Yoichi; Wong, Albert H.C.; Roder, John C.

2009-01-01

Abnormal N-methyl-d-aspartate receptor (NMDAR) function has been implicated in the pathophysiology of schizophrenia. d-serine is an important NMDAR modulator, and to elucidate the role of the d-serine synthesis enzyme serine racemase (Srr) in schizophrenia, we identified and characterized mice with an ENU-induced mutation that results in a complete loss of Srr activity and dramatically reduced d-serine levels. Mutant mice displayed behaviors relevant to schizophrenia, including impairments in prepulse inhibition, sociability and spatial discrimination. Behavioral deficits were exacerbated by an NMDAR antagonist and ameliorated by d-serine or the atypical antipsychotic clozapine. Expression profiling revealed that the Srr mutation influenced several genes that have been linked to schizophrenia and cognitive ability. Transcript levels altered by the Srr mutation were also normalized by d-serine or clozapine treatment. Furthermore, analysis of SRR genetic variants in humans identified a robust association with schizophrenia. This study demonstrates that aberrant Srr function and diminished d-serine may contribute to schizophrenia pathogenesis. PMID:19483194

Small molecule LX2343 ameliorates cognitive deficits in AD model mice by targeting both amyloid β production and clearance.

PubMed

Guo, Xiao-Dan; Sun, Guang-Long; Zhou, Ting-Ting; Xu, Xin; Zhu, Zhi-Yuan; Rukachaisirikul, Vatcharin; Hu, Li-Hong; Shen, Xu

2016-09-01

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. Cell-based assays for screening anti-amyloid compounds were established by assessing Aβ accumulation in HEK293-APP sw 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. LX2343 (5-20 μmol/L) dose-dependently decreased Aβ accumulation in HEK293-APP sw 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 APP Thr668 phosphorylation, thus inhibiting APP cleavage on one hand, and inhibiting BACE1 enzymatic activity with an IC 50 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/PS1 transgenic mice

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. Copyright © 2017 Elsevier B.V. All rights reserved.

Probiotic BIFICO cocktail ameliorates Helicobacter pylori induced gastritis.

PubMed

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

2015-06-07

To determine the protective effect of triple viable probiotics on gastritis induced by Helicobacter pylori (H. pylori) and elucidate the possible mechanisms of protection. 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. 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). Our results suggest that the probiotic

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

Azithromycin ameliorates airway remodeling via inhibiting airway epithelium apoptosis.

PubMed

Liu, Yuanqi; Pu, Yue; Li, Diandian; Zhou, Liming; Wan, Lihong

2017-02-01

Azithromycin can benefit treating allergic airway inflammation and remodeling. In the present study, we hypothesized that azithromycin alleviated airway epithelium injury through inhibiting airway epithelium apoptosis via down regulation of caspase-3 and Bax/Bcl2 ratio in vivo and in vitro. Ovalbumin induced rat asthma model and TGF-β1-induced BEAS-2B cell apoptosis model were established, respectively. In vivo experiments, airway epithelium was stained with hematoxylin and eosin (HE) and periodic acid-Schiff (PAS) to histologically evaluate the airway inflammation and remodeling. Airway epithelium apoptotic index (AI) was further analyzed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), while expression of apoptosis related gene (Bax, Bcl2, Caspase-3) in lungs were measured by qRT-PCR and western blotting, respectively. In vitro experiments, apoptosis were evaluated by Flow cytometry (FCM) and TUNEL. Above apoptosis related gene were also measured by qRT-PCR and western blotting. Compared with the OVA group, azithromycin significantly reduced the inflammation score, peribronchial smooth muscle layer thickness, epithelial thickening and goblet cell metaplasia (P<0.05), and effectively suppressed AI of airway epithelium (P<0.05). Moreover, the increasing mRNA and protein expressions of Caspase-3 and Bax/Bcl-2 ratio in lung tissue were all significantly decreased in azithromycin-treated rats (P<0.05). In vitro, azithromycin significantly suppressed TGF-β1-induced BEAS-2B cells apoptosis (P<0.05) and reversed TGF-β1 elevated Caspase-3 mRNA level and Bax/Bcl-2 ratio (P<0.05). Azithromycin is an attractive treatment option for reducing airway epithelial cell apoptosis by improving the imbalance of Bax/Bcl-2 ratio and inhibiting Caspase-3 level in airway epithelium. Copyright © 2016 Elsevier Inc. All rights reserved.

Amelioration of scopolamine-induced amnesia by phosphatidylserine and curcumin in the day-old chick.

PubMed

Barber, Teresa A; Edris, Edward M; Levinsky, Paul J; Williams, Justin M; Brouwer, Ari R; Gessay, Shawn A

2016-09-01

In the one-trial taste-avoidance task in day-old chicks, acetylcholine receptor activation has been shown to be important for memory formation. Injection of scopolamine produces amnesia, which appears to be very similar in type to that of Alzheimer's disease, which is correlated with low levels of acetylcholine in the brain. Traditional pharmacological treatments of Alzheimer's disease, such as cholinesterase inhibitors and glutamate receptor blockers, improve memory and delay the onset of impairments in memory compared with placebo controls. These agents also ameliorate scopolamine-induced amnesia in the day-old chick trained on the one-trial taste-avoidance task. The present experiments examined the ability of two less traditional treatments for Alzheimer's disease, phosphatidylserine and curcumin, to ameliorate scopolamine-induced amnesia in day-old chicks. The results showed that 37.9 mmol/l phosphatidylserine and 2.7 mmol/l curcumin significantly improved retention in chicks administered scopolamine, whereas lower doses were not effective. Scopolamine did not produce state-dependent learning, indicating that this paradigm in day-old chicks might be a useful one to study the effects of possible Alzheimer's treatments. In addition, chicks administered curcumin or phosphatidylserine showed little avoidance of a bead associated with water reward, indicating that these drugs did not produce response inhibition. The current results extend the findings that some nontraditional memory enhancers can ameliorate memory impairment and support the hypothesis that these treatments might be of benefit in the treatment of Alzheimer's disease.

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.

Parvalbumin and GAD65 Interneuron Inhibition in the Ventral Hippocampus Induces Distinct Behavioral Deficits Relevant to Schizophrenia

PubMed Central

Nguyen, Robin; Morrissey, Mark D.; Mahadevan, Vivek; Cajanding, Janine D.; Woodin, Melanie A.; Yeomans, John S.; Takehara-Nishiuchi, Kaori

2014-01-01

Hyperactivity within the ventral hippocampus (vHPC) has been linked to both psychosis in humans and behavioral deficits in animal models of schizophrenia. A local decrease in GABA-mediated inhibition, particularly involving parvalbumin (PV)-expressing GABA neurons, has been proposed as a key mechanism underlying this hyperactive state. However, direct evidence is lacking for a causal role of vHPC GABA neurons in behaviors associated with schizophrenia. Here, we probed the behavioral function of two different but overlapping populations of vHPC GABA neurons that express either PV or GAD65 by selectively inhibiting these neurons with the pharmacogenetic neuromodulator hM4D. We show that acute inhibition of vHPC GABA neurons in adult mice results in behavioral changes relevant to schizophrenia. Inhibiting either PV or GAD65 neurons produced distinct behavioral deficits. Inhibition of PV neurons, affecting ∼80% of the PV neuron population, robustly impaired prepulse inhibition of the acoustic startle reflex (PPI), startle reactivity, and spontaneous alternation, but did not affect locomotor activity. In contrast, inhibiting a heterogeneous population of GAD65 neurons, affecting ∼40% of PV neurons and 65% of cholecystokinin neurons, increased spontaneous and amphetamine-induced locomotor activity and reduced spontaneous alternation, but did not alter PPI. Inhibition of PV or GAD65 neurons also produced distinct changes in network oscillatory activity in the vHPC in vivo. Together, these findings establish a causal role for vHPC GABA neurons in controlling behaviors relevant to schizophrenia and suggest a functional dissociation between the GABAergic mechanisms involved in hippocampal modulation of sensorimotor processes. PMID:25378161

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...

Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration

PubMed Central

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

2011-01-01

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

Metformin and liraglutide ameliorate high glucose-induced oxidative stress via inhibition of PKC-NAD(P)H oxidase pathway in human aortic endothelial cells.

PubMed

Batchuluun, Battsetseg; Inoguchi, Toyoshi; Sonoda, Noriyuki; Sasaki, Shuji; Inoue, Tomoaki; Fujimura, Yoshinori; Miura, Daisuke; Takayanagi, Ryoichi

2014-01-01

Metformin and glucagon like peptide-1 (GLP-1) prevent diabetic cardiovascular complications and atherosclerosis. However, the direct effects on hyperglycemia-induced oxidative stress in endothelial cells are not fully understood. Thus, we aimed to evaluate the effects of metformin and a GLP-1 analog, liraglutide on high glucose-induced oxidative stress. Production of reactive oxygen species (ROS), activation of protein kinase C (PKC) and NAD(P)H oxidase, and changes in signaling molecules in response to high glucose exposure were evaluated in human aortic endothelial cells with and without treatment of metformin and liraglutide, alone or in combination. PKC-NAD(P)H oxidase pathway was assessed by translocation of GFP-fused PKCβ2 isoform and GFP-fused p47phox, a regulatory subunit of NAD(P)H oxidase, in addition to endogenous PKC phosphorylation and NAD(P)H oxidase activity. High glucose-induced ROS overproduction was blunted by metformin or liraglutide treatment, with a further decrease by a combination of these drugs. Exposure to high glucose caused PKCβ2 translocation and a time-dependent phosphorylation of endogenous PKC but failed to induce its translocation and phosphorylation in the cells treated with metformin and liraglutide. Furthermore, both drugs inhibited p47phox translocation and NAD(P)H oxidase activation, and prevented the high glucose-induced changes in intracellulalr diacylglycerol (DAG) level and phosphorylation of AMP-activated protein kinase (AMPK). A combination of these drugs further enhanced all of these effects. Metformin and liraglutide ameliorate high glucose-induced oxidative stress by inhibiting PKC-NAD(P)H oxidase pathway. A combination of these two drugs provides augmented protective effects, suggesting the clinical usefulness in prevention of diabetic vascular complications. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

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

PubMed

Jiang, Kang-Feng; Zhao, Gan; Deng, Gan-Zhen; Wu, Hai-Chong; Yin, Nan-Nan; Chen, Xiu-Ying; Qiu, Chang-Wei; Peng, Xiu-Li

2017-02-01

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.

Emodin ameliorates high glucose induced-podocyte epithelial-mesenchymal transition in-vitro and in-vivo.

PubMed

Chen, Tingfang; Zheng, Li Yang; Xiao, Wenzhen; Gui, Dingkun; Wang, Xiaoxia; Wang, Niansong

2015-01-01

Epithelial-to-mesenchymal transition (EMT) is a potential pathway leading to podocyte depletion and proteinuria in diabetic kidney disease (DKD). Here, we investigated the protective effects of Emodin (EMO) on high glucose (HG) induced-podocyte EMT in-vitro and in-vivo. Conditionally immortalized mouse podocytes were exposed to HG with 30 μg /ml of EMO and 1 μmol/ml of integrin-linked kinase (ILK) inhibitor QLT0267 for 24 h. Streptozotocin (STZ)-induced diabetic rats were treated with EMO at 20 mg· kg(-1)· d(-1) and QLT0267 at 10 mg· kg(-1)· w(-1) p.o., for 12 weeks. Albuminuria and blood glucose level were measured. Immunohistochemistry, immunofluorescence, western blotting and real-time PCR were used to detect expression of ILK, the epithelial marker of nephrin and the mesenchymal marker of desmin in-vitro and in-vivo. HG increased podocyte ILK and desmin expression while decreased nephrin expression. However, EMO significantly inhibited ILK and desmin expression and partially restored nephrin expression in HG-stimulated podocytes. These in-vitro observations were further confirmed in-vivo. Treatment with EMO for 12 weeks attenuated albuminuria, renal histopathology and podocyte foot process effacement in diabetic rats. EMO also repressed renal ILK and desmin expression, preserved nephrin expression, as well as ameliorated albuminuria in STZ-induced diabetic rats. EMO ameliorated glucose-induced EMT and subsequent podocyte dysfunction partly through ILK and desmin inhibition as well as nephrin upregulatiotion, which might provide a potential novel therapeutic option for DKD. © 2015 S. Karger AG, Basel.

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.

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. Copyright © 2014 John Wiley & Sons, Ltd.

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

Ghrelin ameliorates nerve growth factor Dysmetabolism and inflammation in STZ-induced diabetic rats.

PubMed

Zhao, Yuxing; Shen, Zhaoxing; Zhang, Dongling; Luo, Huiqiong; Chen, Jinliang; Sun, Yue; Xiao, Qian

2017-06-01

Diabetic encephalopathy is characterized by cognitive impairment and neuroinflammation, deficient neurotrophic support, and neuronal and synaptic loss. Ghrelin, a 28 amino acid peptide, is associated with neuromodulation and cognitive improvement, which has been considered as a potential protective agent for several neurodegenerative diseases. Here we sought to investigate the role of ghrelin in preventing diabetic-related neuropathology. We found that ghrelin attenuated astrocytic activation and reduced levels of interleukin-6 and tumor necrosis factor-α in streptozotocin-induced diabetic rats. In addition, ghrelin inhibited p38 mitogen-associated protein kinase activation. The upregulation of nerve growth factor (NGF) precursor and matrix metalloproteinase (MMP)-9 and downregulation of mature NGF and MMP-7 in the diabetic brain were reversed by ghrelin. Treatment with ghrelin elevated synaptophysin expression and synaptic density in diabetic rats. Taken together, our results demonstrate that ghrelin ameliorates diabetes-related neurodegeneration by preventing NGF dysmetabolism and synaptic degeneration through regulating MMP levels as well as inhibiting neuroinflammation.

Carbenoxolone Treatment Ameliorated Metabolic Syndrome in WNIN/Ob Obese Rats, but Induced Severe Fat Loss and Glucose Intolerance in Lean Rats

PubMed Central

Prasad Sakamuri, Siva Sankara Vara; Sukapaka, Mahesh; Prathipati, Vijay Kumar; Nemani, Harishankar; Putcha, Uday Kumar; Pothana, Shailaja; Koppala, Swarupa Rani; Ponday, Lakshmi Raj Kumar; Acharya, Vani; Veetill, Giridharan Nappan; Ayyalasomayajula, Vajreswari

2012-01-01

Background 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates local glucocorticoid action in tissues by catalysing conversion of inactive glucocorticoids to active glucocorticoids. 11β-HSD1 inhibition ameliorates obesity and associated co-morbidities. Here, we tested the effect of 11β-HSD inhibitor, carbenoxolone (CBX) on obesity and associated comorbidities in obese rats of WNIN/Ob strain, a new animal model for genetic obesity. Methodology/Principal Findings Subcutaneous injection of CBX (50 mg/kg body weight) or volume-matched vehicle was given once daily for four weeks to three month-old WNIN/Ob lean and obese rats (n = 6 for each phenotype and for each treatment). Body composition, plasma lipids and hormones were assayed. Hepatic steatosis, adipose tissue morphology, inflammation and fibrosis were also studied. Insulin resistance and glucose intolerance were determined along with tissue glycogen content. Gene expressions were determined in liver and adipose tissue. CBX significantly inhibited 11β-HSD1 activity in liver and adipose tissue of WNIN/Ob lean and obese rats. CBX significantly decreased body fat percentage, hypertriglyceridemia, hypercholesterolemia, insulin resistance in obese rats. CBX ameliorated hepatic steatosis, adipocyte hypertrophy, adipose tissue inflammation and fibrosis in obese rats. Tissue glycogen content was significantly decreased by CBX in liver and adipose tissue of obese rats. Severe fat loss and glucose- intolerance were observed in lean rats after CBX treatment. Conclusions/Significance We conclude that 11β-HSD1 inhibition by CBX decreases obesity and associated co-morbidities in WNIN/Ob obese rats. Our study supports the hypothesis that inhibition of 11β-HSD1 is a key strategy to treat metabolic syndrome. Severe fat loss and glucose -intolerance by CBX treatment in lean rats suggest that chronic 11β-HSD1 inhibition may lead to insulin resistance in normal conditions. PMID:23284633

Prenatal phencyclidine treatment induces behavioral deficits through impairment of GABAergic interneurons in the prefrontal cortex.

PubMed

Toriumi, Kazuya; Oki, Mika; Muto, Eriko; Tanaka, Junko; Mouri, Akihiro; Mamiya, Takayoshi; Kim, Hyoung-Chun; Nabeshima, Toshitaka

2016-06-01

We previously reported that prenatal treatment with phencyclidine (PCP) induces glutamatergic dysfunction in the prefrontal cortex (PFC), leading to schizophrenia-like behavioral deficits in adult mice. However, little is known about the prenatal effect of PCP treatment on other types of neurons. We focused on γ-aminobutyric acid (GABA)-ergic interneurons and evaluated the effect of prenatal PCP exposure on the neurodevelopment of GABAergic interneurons in the PFC. PCP was administered at the dose of 10 mg/kg/day to pregnant dams from embryonic day 6.5 to 18.5. After the pups were reared to adult, we analyzed their GABAergic system in the PFC using immunohistological, biochemical, and behavioral analyses in adulthood. The prenatal PCP treatment decreased the density of parvalbumin-positive cells and reduced the expression level of glutamic acid decarboxylase 67 (GAD67) and GABA content of the PFC in adults. Additionally, prenatal PCP treatment induced behavioral deficits in adult mice, such as hypersensitivity to PCP and prepulse inhibition (PPI) deficits. These behavioral deficits were ameliorated by pretreatment with the GABAB receptor agonist baclofen. Furthermore, the density of c-Fos-positive cells was decreased after the PPI test in the PFC of mice treated with PCP prenatally, and this effect was ameliorated by pretreatment with baclofen. These findings suggest that prenatal treatment with PCP induced GABAergic dysfunction in the PFC, which caused behavioral deficits.

GLAST Deficiency in Mice Exacerbates Gap Detection Deficits in a Model of Salicylate-Induced Tinnitus

PubMed Central

Yu, Hong; Vikhe Patil, Kim; Han, Chul; Fabella, Brian; Canlon, Barbara; Someya, Shinichi; Cederroth, Christopher R.

2016-01-01

Gap detection or gap pre-pulse inhibition of the acoustic startle (GPIAS) has been successfully used in rat and guinea pig models of tinnitus, yet this system has been proven to have low efficacy in CBA mice, with low basal GPIAS and subtle tinnitus-like effects. Here, we tested five mouse strains (CBA, BalbC, CD-1, C57BL/6 and 129sv) for pre-pulse inhibition (PPI) and gap detection with varying interstimulus intervals (ISI) and found that mice from a CBA genetic background had the poorest capacities of suppressing the startle response in the presence of a pre-pulse or a gap. CD-1 mice displayed variable responses throughout all ISI. Interestingly, C57BL/6, 129sv and BalbC showed efficient suppression with either pre-pulses or gaps with shorter ISI. The glutamate aspartate transporter (GLAST) is expressed in support cells from the cochlea and buffers the excess of glutamate. We hypothesized that loss of GLAST function could sensitize the ear to tinnitus-inducing agents, such as salicylate. Using shorter ISI to obtain a greater dynamic range to assess tinnitus-like effects, we found that disruption of gap detection by salicylate was exacerbated across various intensities of a 32-kHz narrow band noise gap carrier in GLAST knockout (KO) mice when compared to their wild-type (WT) littermates. Auditory brainstem responses (ABR) and distortion-product otoacoustic emission (DPOAE) were performed to evaluate the effects on hearing functions. Salicylate caused greater auditory threshold shifts (near 15 dB) in GLAST KO mice than in WT mice across all tested frequencies, despite similarly reduced DPOAE. Despite these changes, inhibition using broad-band gap carriers and 32 kHz pre-pulses were not affected. Our study suggests that GLAST deficiency could become a useful experimental model to decipher the mechanisms underlying drug-induced tinnitus. Future studies addressing the neurological correlates of tinnitus in this model could provide additional insights into the

GLAST Deficiency in Mice Exacerbates Gap Detection Deficits in a Model of Salicylate-Induced Tinnitus.

PubMed

Yu, Hong; Vikhe Patil, Kim; Han, Chul; Fabella, Brian; Canlon, Barbara; Someya, Shinichi; Cederroth, Christopher R

2016-01-01

Gap detection or gap pre-pulse inhibition of the acoustic startle (GPIAS) has been successfully used in rat and guinea pig models of tinnitus, yet this system has been proven to have low efficacy in CBA mice, with low basal GPIAS and subtle tinnitus-like effects. Here, we tested five mouse strains (CBA, BalbC, CD-1, C57BL/6 and 129sv) for pre-pulse inhibition (PPI) and gap detection with varying interstimulus intervals (ISI) and found that mice from a CBA genetic background had the poorest capacities of suppressing the startle response in the presence of a pre-pulse or a gap. CD-1 mice displayed variable responses throughout all ISI. Interestingly, C57BL/6, 129sv and BalbC showed efficient suppression with either pre-pulses or gaps with shorter ISI. The glutamate aspartate transporter (GLAST) is expressed in support cells from the cochlea and buffers the excess of glutamate. We hypothesized that loss of GLAST function could sensitize the ear to tinnitus-inducing agents, such as salicylate. Using shorter ISI to obtain a greater dynamic range to assess tinnitus-like effects, we found that disruption of gap detection by salicylate was exacerbated across various intensities of a 32-kHz narrow band noise gap carrier in GLAST knockout (KO) mice when compared to their wild-type (WT) littermates. Auditory brainstem responses (ABR) and distortion-product otoacoustic emission (DPOAE) were performed to evaluate the effects on hearing functions. Salicylate caused greater auditory threshold shifts (near 15 dB) in GLAST KO mice than in WT mice across all tested frequencies, despite similarly reduced DPOAE. Despite these changes, inhibition using broad-band gap carriers and 32 kHz pre-pulses were not affected. Our study suggests that GLAST deficiency could become a useful experimental model to decipher the mechanisms underlying drug-induced tinnitus. Future studies addressing the neurological correlates of tinnitus in this model could provide additional insights into the

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. Copyright © 2015. Published by Elsevier B.V.

Methyl Salicylate Lactoside Protects Neurons Ameliorating Cognitive Disorder Through Inhibiting Amyloid Beta-Induced Neuroinflammatory Response in Alzheimer’s Disease

PubMed Central

Li, Jinze; Ma, Xiaowei; Wang, Yu; Chen, Chengjuan; Hu, Min; Wang, Linlin; Fu, Junmin; Shi, Gaona; Zhang, Dongming; Zhang, Tiantai

2018-01-01

Neuroinflammatory reactions mediated by microglia and astrocytes have been shown to play a key role in early progression of Alzheimer’s disease (AD). Increased evidences have demonstrated that neurons exacerbate local inflammatory reactions by producing inflammatory mediators and act as an important participant in the pathogenesis of AD. Methyl salicylate lactoside (MSL) is an isolated natural product that is part of a class of novel non-steroidal anti-inflammatory drugs (NSAID). In our previous studies, we demonstrated that MSL exhibited therapeutic effects on arthritis-induced mice and suppressed the activation of glial cells. In the current study, we investigated the effects of MSL on cognitive function and neuronal protection induced by amyloid-beta peptides (Aβ) and explored potential underlying mechanisms involved. Amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice were used to evaluate the effects of MSL through behavioral testing and neuronal degenerative changes. In addition, copper-injured APP Swedish mutation overexpressing SH-SY5Y cells were used to determine the transduction of cyclooxygenase (COX) and mitogen-activated protein kinase (MAPK) pathways. Our results indicated that at an early stage, MSL treatment ameliorated cognitive impairment and neurodegeneration in APP/PS1 mice. Moreover, in an in vitro AD model, MSL treatment protected injured cells by increasing cell viability, improving mitochondrial dysfunction, and decreasing oxidative damage. In addition, MSL inhibited the phosphorylated level of c-Jun N-terminal kinase (JNK) and p38 MAPK, and suppressed the expression of COX-1/2. As a novel NSAIDs and used for the treatment in early stage of AD, MSL clearly demonstrated cognitive preservation by protecting neurons via a pleiotropic anti-inflammatory effect in the context of AD-associated deficits. Therefore, early treatment of anti-inflammatory therapy may be an effective strategy for treating AD. PMID:29636677

Angiotensin II receptor blocker valsartan ameliorates cardiac fibrosis partly by inhibiting miR-21 expression in diabetic nephropathy mice.

PubMed

Wang, Jinyang; Duan, Lijun; Gao, Yanbin; Zhou, Shuhong; Liu, Yongming; Wei, Suhong; An, Siqin; Liu, Jing; Tian, Liming; Wang, Shaocheng

2017-12-09

Cardiac fibrosis with diabetic nephropathy (DN) is one of major diabetic complications. miR-21 and MMP-9 were closely associated with fibrosis diseases. Angiotensin II receptor blockers (ARB) have cardioprotective effects. However, it remains unclear whether miR-21 was involved in the mechanism of cardiac fibrosis with DN by target MMP-9 and ARB ameliorates cardiac fibrosis partly by inhibiting miR-21 expression. In this study, In Situ Hybridization(ISH), RT-PCR, cell transfection, western blotting and laser confocal telescope were used, respectively. ISH showed that miR-21, concentrated in cytoplasmic foci in the proximity of the nucleus, was mainly localized in cardiac fibroblasts and at relatively low levels in cardiomyocytes within cardiac tissue with DN. RT-PCR showed that miR-21 expression was significantly enhanced in cardiac tissue with DN, accompanied by the increase of col-IV, FN, CVF, PVCA, LVMI, HWI and NT-pro-BNP (p < 0.05). Bioinformatics analysis and Luciferase reporter gene assays showed that MMP-9 was a validated target of miR-21. Furthermore, cell transfection experiments showed that miR-21 overexpression directly decreased MMP-9 expression. Interestingly, miR-21 levels in cardiac tissue was positively correlated with ACR (r = -0.870, P = 0.003), whereas, uncorrelated with SBP, HbA1C and T-Cho (p > 0.05). More importantly, ARB can significantly decrease miR-21 expression in cardiac tissue, cardiac fibroblasts and serum. Overall, our results suggested that miR-21 may contribute to the pathogenesis of cardiac fibrosis with DN by target MMP-9, and that miR-21 may be a new possible therapeutic target for ARB in cardiac fibrosis with DN. Copyright © 2017. Published by Elsevier B.V.

Alendronate inhalation ameliorates elastase-induced pulmonary emphysema in mice by induction of apoptosis of alveolar macrophages.

PubMed

Ueno, Manabu; Maeno, Toshitaka; Nishimura, Satoshi; Ogata, Fusa; Masubuchi, Hiroaki; Hara, Kenichiro; Yamaguchi, Kouichi; Aoki, Fumiaki; Suga, Tatsuo; Nagai, Ryozo; Kurabayashi, Masahiko

2015-03-10

Alveolar macrophages play a crucial role in the pathogenesis of emphysema, for which there is currently no effective treatment. Bisphosphonates are widely used to treat osteoclast-mediated bone diseases. Here we show that delivery of the nitrogen-containing bisphosphonate alendronate via aerosol inhalation ameliorates elastase-induced emphysema in mice. Inhaled, but not orally ingested, alendronate inhibits airspace enlargement after elastase instillation, and induces apoptosis of macrophages in bronchoalveolar fluid via caspase-3- and mevalonate-dependent pathways. Cytometric analysis indicates that the F4/80(+)CD11b(high)CD11c(mild) population characterizing inflammatory macrophages, and the F4/80(+)CD11b(mild)CD11c(high) population defining resident alveolar macrophages take up substantial amounts of the bisphosphonate imaging agent OsteoSense680 after aerosol inhalation. We further show that alendronate inhibits macrophage migratory and phagocytotic activities and blunts the inflammatory response of alveolar macrophages by inhibiting nuclear factor-κB signalling. Given that the alendronate inhalation effectively induces apoptosis in both recruited and resident alveolar macrophages, we suggest this strategy may have therapeutic potential for the treatment of emphysema.

Psilocybin-Induced Deficits in Automatic and Controlled Inhibition are Attenuated by Ketanserin in Healthy Human Volunteers

PubMed Central

Quednow, Boris B; Kometer, Michael; Geyer, Mark A; Vollenweider, Franz X

2012-01-01

The serotonin-2A receptor (5-HT2AR) has been implicated in the pathogenesis of schizophrenia and related inhibitory gating and behavioral inhibition deficits of schizophrenia patients. The hallucinogen psilocybin disrupts automatic forms of sensorimotor gating and response inhibition in humans, but it is unclear so far whether the 5-HT2AR or 5-HT1AR agonist properties of its bioactive metabolite psilocin account for these effects. Thus, we investigated whether psilocybin-induced deficits in automatic and controlled inhibition in healthy humans could be attenuated by the 5-HT2A/2CR antagonist ketanserin. A total of 16 healthy participants received placebo, ketanserin (40 mg p.o.), psilocybin (260 μg/kg p.o.), or psilocybin plus ketanserin in a double-blind, randomized, and counterbalanced order. Sensorimotor gating was measured by prepulse inhibition (PPI) of the acoustic startle response. The effects on psychopathological core dimensions and behavioral inhibition were assessed by the altered states of consciousness questionnaire (5D-ASC), and the Color-Word Stroop Test. Psilocybin decreased PPI at short lead intervals (30 ms), increased all 5D-ASC scores, and selectively increased errors in the interference condition of the Stroop Test. Stroop interference and Stroop effect of the response latencies were increased under psilocybin as well. Psilocybin-induced alterations were attenuated by ketanserin pretreatment, whereas ketanserin alone had no significant effects. These findings suggest that the disrupting effects of psilocybin on automatic and controlled inhibition processes are attributable to 5-HT2AR stimulation. Sensorimotor gating and attentional control deficits of schizophrenia patients might be due to changes within the 5-HT2AR system. PMID:21956447

Costunolide ameliorates lipoteichoic acid-induced acute lung injury via attenuating MAPK signaling pathway.

PubMed

Chen, Zhengxu; Zhang, Dan; Li, Man; Wang, Baolong

2018-06-12

Lipoteichoic acid (LTA)-induced acute lung injury (ALI) is an experimental model for mimicking Gram-positive bacteria-induced pneumonia that is a refractory disease with lack of effective medicines. Here, we reported that costunolide, a sesquiterpene lactone, ameliorated LTA-induced ALI. Costunolide treatment reduced LTA-induced neutrophil lung infiltration, cytokine and chemokine production (TNF-α, IL-6 and KC), and pulmonary edema. In response to LTA challenge, treatment with costunolide resulted less iNOS expression and produced less inflammatory cytokines in bone marrow derived macrophages (BMDMs). Pretreatment with costunolide also attenuated the LTA-induced the phosphorylation of p38 MAPK and ERK in BMDMs. Furthermore, costunolide treatment reduced the phosphorylation of TAK1 and inhibited the interaction of TAK1 with Tab1. In conclusion, we have demonstrated that costunolide protects against LTA-induced ALI via inhibiting TAK1-mediated MAPK signaling pathway, and our studies suggest that costunolide is a promising agent for treatment of Gram-positive bacteria-mediated pneumonia. Copyright © 2018 Elsevier B.V. All rights reserved.

Continuous Blood Purification Ameliorates Multiple Organ Failure Through Inhibiting the Activation of the P38 MAPK Signaling Pathway in a Rat Model.

PubMed

Ling, Lan; Wen, Qian-Kuan; Zhang, Shan-Hong; Zhi, Li-Da; Li, Hong; Li, Gang; Zhang, Wen-Jia

2018-06-07

Multiple organ failure (MOF) is a primary threat to the survival of patients with systemic inflammation. Blood purification is employed in the treatment of MOF, as an artificial kidney or artificial liver. This study focuses on the effects of continuous blood purification (CBP) on ameliorating MOF through regulating the p38 mitogen-activated protein kinase (MAPK) signaling pathway in a rat model. A rat model of MOF was successfully established by endotoxin injection after hemorrhagic shock resuscitation. The mRNA expressions of inducible nitric oxide synthase (iNOS) and p38 MAPK of liver, kidney, and lung tissues in each group were measured by RT-qPCR at each measuring time point. To evaluate the activation of p38 MAPK signaling pathway, protein levels of phosphorylated p38 (p-p38) MAPK and p38 MAPK was measured by western blot analysis. The serum levels of nitric oxide and TNF-α were determined. After CBP treatment, the levels of SGPT, SGOT, Cr, and BUN were significantly declined, while the PaO2 value was increased. Expressions of p38 MAPK mRNA, iNOS mRNA, p-p38 MAPK protein and p38 MAPK protein, and nitric oxide and TNF-α levels were markedly elevated in MOF, an effect blunted by CPB. Meanwhile, pathological sections of liver, kidney, and lung tissues after CPB treatment ameliorated swelling and inflammation. Our study proved that CBP could downregulate the p38 MAPK signaling pathway, suppress iNOS expression, reduced the serum levels of nitric oxide and TNF-α, thus ameliorate symptom of MOF. © 2018 The Author(s). Published by S. Karger AG, Basel.

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.

Nyctanthes arbor-tristis Ameliorated FCA-Induced Experimental Arthritis: A Comparative Study among Different Extracts

PubMed Central

Uroos, Maliha; Sattar, Shumaila; Umer, Nigarish; Sharif, Ahsan

2017-01-01

Nyctanthes arbor-tristis (NAT) is commonly used traditionally for the treatment of rheumatism and inflammatory diseases. Current study evaluates the antiarthritic potential of NAT using Freund's adjuvant-induced arthritic rat model. Treatments with methanolic, ethyl acetate, and n-hexane extracts were continued for consecutive 20 days. Macroscopic arthritic scoring and water displacement plethysmometry were used to evaluate arthritic development. Hematological and biochemical parameters were investigated and ankle joints were processed for histopathological evaluation. Qualitative phytochemical analysis and GC-MS analysis were conducted for identification of constituents. NAT extracts suppressed arthritic scoring, paw edema, infiltration of inflammatory cells, pannus formation, and bone erosion. The plant extracts ameliorated total leukocytes and platelet counts and nearly normalized red blood cells (RBC) counts and hemoglobin (Hb) content. The extracts were found safe in terms of hepatotoxicity and nephrotoxicity as determined by aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, and urea levels. Comparative analysis showed that ethyl acetate extract produced the highest inhibition of paw edema. The major constituents found in ethyl acetate extract can be classified into three major classes, that is, terpenes, terpenoids, fatty acids, and iridoid glycosides. Current study showed that Nyctanthes arbor-tristis ameliorated experimental rheumatoid arthritis and ethyl acetate extract possessed the highest inhibitory activity. PMID:28676830

Inhibition of SHP2 ameliorates the pathogenesis of systemic lupus erythematosus

PubMed Central

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

2016-01-01

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

Inhibition of SHP2 ameliorates the pathogenesis of systemic lupus erythematosus.

PubMed

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

2016-06-01

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

Bcl-2 protects tubular epithelial cells from ischemia reperfusion injury by inhibiting apoptosis.

PubMed

Suzuki, Chigure; Isaka, Yoshitaka; Shimizu, Shigeomi; Tsujimoto, Yoshihide; Takabatake, Yoshitsugu; Ito, Takahito; Takahara, Shiro; Imai, Enyu

2008-01-01

Ischemia followed by reperfusion leads to severe organ injury and dysfunction. Inflammation is considered to be the most important cause of graft dysfunction in kidney transplantation subjected to ischemia. The mechanism that triggers inflammation and renal injury after ischemia remains to be elucidated; however, cellular stress may induce apoptosis during the first hours and days after transplantation, which might play a crucial role in early graft dysfunction. Bcl-2 is known to inhibit apoptosis induced by the etiological factors promoting ischemia and reperfusion injury. Accordingly, we hypothesized that an augmentation of the antiapoptotic factor Bcl-2 may thus protect tubular epithelial cells by inhibiting apoptosis, thereby ameliorating the subsequent tubulointerstitial injury. We examined the effects of Bcl-2 overexpression on ischemia-reperfusion (I/R) injury using Bcl-2 transgenic mice (Bcl-2 TG) and their wild-type littermates (WT). To investigate the effects of I/R injury, the left renal artery and vein were clamped for 45 min, followed by reperfusion for 0-96 h. Bcl-2 TG exhibited decreased active caspase protein in the tubular cells, which led to a reduction in TUNEL-positive apoptotic cells. Consequently, interstitial fibrosis and phenotypic changes were ameliorated in Bcl-2 TG. In conclusion, Bcl-2 augmentation protected renal tubular epithelial cells from I/R, and subsequent interstitial injury by inhibiting tubular apoptosis.

Osthole, a Coumadin Analog from Cnidium monnieri (L.) Cusson, Ameliorates Nucleus Pulposus-Induced Radicular Inflammatory Pain by Inhibiting the Activation of Extracellular Signal-Regulated Kinase in Rats.

PubMed

Wu, Hai-Xuan; Wang, Yi-Min; Xu, Hui; Wei, Ming; He, Qiu-Lan; Li, Mei-Na; Sun, Lai-Bao; Cao, Ming-Hui

2017-01-01

This study was aimed at assessing the role of extracellular signal regulated kinase (ERK) in mechanical allodynia resulting from lumbar disc herniation (LDH) and exploring the osthole's anti-nociceptive effect on ERK activation. Radicular pain was generated by applying nucleus pulposus (NP) to the L5 dorsal root ganglion (DRG). Allodynia was measured using Von Frey filaments to calculate the mechanical pain threshold. Phosphorylated ERK and total ERK protein in the lumbar spinal dorsal horn was detected by using the Western blot technique. Cyclooxygenase 2 (COX-2) mRNA was assessed by real-time reverse-transcription polymerase chain reaction. The application of NP to L5 DRG induced mechanical hypersensitivity which lasted for at least 28 days, and a significant increase of ERK phosphorylation in the ipsilateral spinal dorsal horn from postoperative day (POD) 1 to POD 21. ERK inhibitor attenuated NP-induced hyperalgesia compared to the dimethyl sulfoxide-(vehicle control) administered group (p < 0.05). Epidural treatment with osthole could ameliorate NP-evoked hyperalgesia by suppressing the activation of ERK rather than decreasing the expression of ERK protein. Osthole could also inhibit the increased expression of COX-2 mRNA in spinal dorsal horn, which was a known downstream effect of ERK signaling pathway. Our results suggest that ERK activation in the spinal dorsal horn plays a vital role in NP-evoked hyperalgesia. Osthole exerts analgesic effect on radicular inflammatory pain in LDH rat model, by down-regulating the mRNA expression of the target gene of COX-2 via inhibiting ERK activation in the spinal dorsal horn. © 2017 S. Karger AG, Basel.

STAT6 deficiency ameliorates Graves' disease severity by suppressing thyroid epithelial cell hyperplasia.

PubMed

Jiang, Xuechao; Zha, Bingbing; Liu, Xiaoming; Liu, Ronghua; Liu, Jun; Huang, Enyu; Qian, Tingting; Liu, Jiajing; Wang, Zhiming; Zhang, Dan; Wang, Luman; Chu, Yiwei

2016-12-01

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.

Oral intake of hydrogen-rich water ameliorated chlorpyrifos-induced neurotoxicity in rats

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

Wang, Tingting; Zhao, Ling; Liu, Mengyu

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 increasedmore » 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

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

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

Lim, J.C.-W.

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

Metformin ameliorates high uric acid-induced insulin resistance in skeletal muscle cells.

PubMed

Yuan, Huier; Hu, Yaqiu; Zhu, Yuzhang; Zhang, Yongneng; Luo, Chaohuan; Li, Zhi; Wen, Tengfei; Zhuang, Wanling; Zou, Jinfang; Hong, Liangli; Zhang, Xin; Hisatome, Ichiro; Yamamoto, Tetsuya; Cheng, Jidong

2017-03-05

Hyperuricemia occurs together with abnormal glucose metabolism and insulin resistance. Skeletal muscle is an important organ of glucose uptake, disposal, and storage. Metformin activates adenosine monophosphate-activated protein kinase (AMPK) to regulate insulin signaling and promote the translocation of glucose transporter type 4 (GLUT4), thereby stimulating glucose uptake to maintain energy balance. Our previous study showed that high uric acid (HUA) induced insulin resistance in skeletal muscle tissue. However, the mechanism of metformin ameliorating UA-induced insulin resistance in muscle cells is unknown and we aimed to determine it. In this study, differentiated C2C12 cells were exposed to UA (15 mg/dl), then reactive oxygen species (ROS) was detected with DCFH-DA and glucose uptake with 2-NBDG. The levels of phospho-insulin receptor substrate 1 (IRS1; Ser307), phospho-AKT (Ser473) and membrane GLUT4 were examined by western blot analysis. The impact of metformin on UA-induced insulin resistance was monitored by adding Compound C, an AMPK inhibitor, and LY294002, a PI3K/AKT inhibitor. Our data indicate that UA can increase ROS production, inhibit IRS1-AKT signaling and insulin-stimulated glucose uptake, and induce insulin resistance in C2C12 cells. Metformin can reverse this process by increasing intracellular glucose uptake and ameliorating UA-induced insulin resistance. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

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. Copyright © 2013 Elsevier GmbH. All rights reserved.

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.

27 CFR 24.304 - Chaptalization (Brix adjustment) and amelioration record.

Code of Federal Regulations, 2013 CFR

2013-04-01

... or wine is ameliorated, the quantity of pure dry sugar added to juice will be included as..., the quantity of pure dry sugar added for chaptalization is not considered ameliorating material... quantities will be recorded in wine gallons, and, where sugar is used, the quantity will be determined either...

27 CFR 24.304 - Chaptalization (Brix adjustment) and amelioration record.

Code of Federal Regulations, 2014 CFR

2014-04-01

... or wine is ameliorated, the quantity of pure dry sugar added to juice will be included as..., the quantity of pure dry sugar added for chaptalization is not considered ameliorating material... quantities will be recorded in wine gallons, and, where sugar is used, the quantity will be determined either...

27 CFR 24.304 - Chaptalization (Brix adjustment) and amelioration record.

Code of Federal Regulations, 2012 CFR

2012-04-01

... or wine is ameliorated, the quantity of pure dry sugar added to juice will be included as..., the quantity of pure dry sugar added for chaptalization is not considered ameliorating material... quantities will be recorded in wine gallons, and, where sugar is used, the quantity will be determined either...

27 CFR 24.304 - Chaptalization (Brix adjustment) and amelioration record.

Code of Federal Regulations, 2010 CFR

2010-04-01

... or wine is ameliorated, the quantity of pure dry sugar added to juice will be included as..., the quantity of pure dry sugar added for chaptalization is not considered ameliorating material... quantities will be recorded in wine gallons, and, where sugar is used, the quantity will be determined either...

27 CFR 24.304 - Chaptalization (Brix adjustment) and amelioration record.

Code of Federal Regulations, 2011 CFR

2011-04-01

... or wine is ameliorated, the quantity of pure dry sugar added to juice will be included as..., the quantity of pure dry sugar added for chaptalization is not considered ameliorating material... quantities will be recorded in wine gallons, and, where sugar is used, the quantity will be determined either...

Quercetin ameliorates kidney injury and fibrosis by modulating M1/M2 macrophage polarization.

PubMed

Lu, Hong; Wu, Lianfeng; Liu, Leping; Ruan, Qingqing; Zhang, Xing; Hong, Weilong; Wu, Shijia; Jin, Guihua; Bai, Yongheng

2018-05-15

Interstitial inflammation is the main pathological feature in kidneys following injury, and the polarization of macrophages is involved in the process of inflammatory injury. Previous studies have shown that quercetin has a renal anti-inflammatory activity, but the potential molecular mechanism remains unknown. In obstructive kidneys, administration of quercetin inhibited tubulointerstitial injury and reduced the synthesis and release of inflammatory factors. Further study revealed that quercetin inhibited the infiltration of CD68+ macrophages in renal interstitium. Moreover, the decrease in levels of iNOS and IL-12, as well as the proportion of F4/80+/CD11b+/CD86+ macrophages, indicated quercetin-mediated inhibition of M1 macrophage polarization in the injured kidneys. In cultured macrophages, lipopolysaccharide-induced inflammatory polarization was suppressed by quercetin treatment, resulting in the reduction of the release of inflammatory factors. Notably, quercetin-induced inhibitory effects on inflammatory macrophage polarization were associated with down-regulated activities of NF-κB p65 and IRF5, and thus led to the inactivation of upstream signaling TLR4/Myd88. Interestingly, quercetin also inhibited the polarization of F4/80+/CD11b+/CD206+ M2 macrophages, and reduced excessive accumulation of extracellular matrix and interstitial fibrosis by antagonizing the TGF-β1/Smad2/3 signaling. Thus, quercetin ameliorates kidney injury via modulating macrophage polarization, and may have therapeutic potential for patients with kidney injury. Copyright © 2018 Elsevier Inc. All rights reserved.

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

PubMed

Shao, Shiying; Zhang, Xiaojie; Zhang, Muxun

2016-09-09

Excess 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) may be implicated in the development of obesity related metabolic disorders. The present study measured the expression level of 11β-HSD1 in visceral adipose tissues from 23 patients undergoing abdominal operation. Correlation of 11β-HSD1 expression with BMI, waist-to-hip ratio (WHR), HOMA-IR, and serum lipids was evaluated by spearman correlation analysis. High-fat diet-induced obese (DIO) rats were orally dosed with BVT.2733 for 4 weeks. Weight, plasma insulin, and lipids were detected at the end of the treatment. The effects of 11β-HSD1 inhibition on the key insulin-signaling cascade and adipocytokines were measured by western blot and ELISA respectively. 11β-HSD1 was increased in patients with central obesity, the expression level of which was closely related with WHR (r = 0.5851), BMI (r = 0.4952), and HOMA-IR (r = 0.4637). Obesity related insulin resistance in high-fat DIO rats, as reflected by a marked decrease in IRS-1, IRS-2, GLUT4, and PI3K, could be attenuated by 11β-HSD1 inhibition. Furthermore, the down-regulation of 11β-HSD1 could correct the disordered profiles of adipocytokines including adiponectin, IL-6, and TNF-α. These findings indicated that 11β-HSD1 inhibition can give a potential benefit in reducing obesity and lowering insulin resistance by modulating the insulin-signaling pathway and adipocytokine production. Copyright © 2016. Published by Elsevier Inc.

Environmental enrichment reduces innate anxiety with no effect on depression-like behaviour in mice lacking the serotonin transporter.

PubMed

Rogers, Jake; Li, Shanshan; Lanfumey, Laurence; Hannan, Anthony J; Renoir, Thibault

2017-08-14

Along with being the main target of many antidepressant medications, the serotonin transporter (5-HTT) is known to be involved in the pathophysiology of depression and anxiety disorders. In line with this, mice with varying 5-HTT genotypes are invaluable tools to study depression- and anxiety-like behaviours as well as the mechanisms mediating potential therapeutics. There is clear evidence that both genetic and environmental factors play a role in the aetiology of psychiatric disorders. In that regard, housing paradigms which seek to enhance cognitive stimulation and physical activity have been shown to exert beneficial effects in animal models of neuropsychiatric disorders. In the present study, we examined the effects of environmental enrichment on affective-like behaviours and sensorimotor gating function of 5-HTT knock-out (KO) mice. Using the elevated-plus maze and the light-dark box, we found that environmental enrichment ameliorated the abnormal innate anxiety of 5-HTT KO mice on both tests. In contrast, environmental enrichment did not rescue the depression-like behaviour displayed by 5-HTT KO mice in the forced-swim test. Finally, measuring pre-pulse inhibition, we found no effect of genotype or treatment on sensorimotor gating. In conclusion, our data suggest that environmental enrichment specifically reduces innate anxiety of 5-HTT KO mice with no amelioration of the depression-like behaviour. This has implications for the current use of clinical interventions for patients with symptoms of both anxiety and depression. Copyright © 2017 Elsevier B.V. All rights reserved.

Psilocybin-induced deficits in automatic and controlled inhibition are attenuated by ketanserin in healthy human volunteers.

PubMed

Quednow, Boris B; Kometer, Michael; Geyer, Mark A; Vollenweider, Franz X

2012-02-01

The serotonin-2A receptor (5-HT(2A)R) has been implicated in the pathogenesis of schizophrenia and related inhibitory gating and behavioral inhibition deficits of schizophrenia patients. The hallucinogen psilocybin disrupts automatic forms of sensorimotor gating and response inhibition in humans, but it is unclear so far whether the 5-HT(2A)R or 5-HT(1A)R agonist properties of its bioactive metabolite psilocin account for these effects. Thus, we investigated whether psilocybin-induced deficits in automatic and controlled inhibition in healthy humans could be attenuated by the 5-HT(2A/2C)R antagonist ketanserin. A total of 16 healthy participants received placebo, ketanserin (40 mg p.o.), psilocybin (260 μg/kg p.o.), or psilocybin plus ketanserin in a double-blind, randomized, and counterbalanced order. Sensorimotor gating was measured by prepulse inhibition (PPI) of the acoustic startle response. The effects on psychopathological core dimensions and behavioral inhibition were assessed by the altered states of consciousness questionnaire (5D-ASC), and the Color-Word Stroop Test. Psilocybin decreased PPI at short lead intervals (30 ms), increased all 5D-ASC scores, and selectively increased errors in the interference condition of the Stroop Test. Stroop interference and Stroop effect of the response latencies were increased under psilocybin as well. Psilocybin-induced alterations were attenuated by ketanserin pretreatment, whereas ketanserin alone had no significant effects. These findings suggest that the disrupting effects of psilocybin on automatic and controlled inhibition processes are attributable to 5-HT(2A)R stimulation. Sensorimotor gating and attentional control deficits of schizophrenia patients might be due to changes within the 5-HT(2A)R system.

SERCA2a upregulation ameliorates cellular alternans induced by metabolic inhibition.

PubMed

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

2016-04-15

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

SERCA2a upregulation ameliorates cellular alternans induced by metabolic inhibition

PubMed Central

Stary, Victoria; Puppala, Dheeraj; Scherrer-Crosbie, Marielle; Dillmann, Wolfgang H.

2016-01-01

Cardiac alternans has been associated with the incidence of ventricular tachyarrhythmias and sudden cardiac death. The aim of this study was to investigate the effect of impaired mitochondrial function in the genesis of cellular alternans and to examine whether modulating the sarcoplasmic reticulum (SR) Ca2+ ameliorates the level of alternans. Cardiomyocytes isolated from control and doxycyline-induced sarco(endo)plasmic reticulum Ca2+-ATPase 2a (SERCA2a)-upregulated mice were loaded with two different Ca2+ indicators to selectively measure mitochondrial and cytosolic Ca2+ using a custom-made fluorescence photometry system. The degree of alternans was defined as the alternans ratio (AR) [1 − (small Ca2+ intensity)/(large Ca2+ intensity)]. Blocking of complex I and II, cytochrome-c oxidase, F0F1 synthase, α-ketoglutarate dehydrogenase of the electron transport chain, increased alternans in both control and SERCA2a mice (P < 0.01). Changes in AR in SERCA2a-upregulated mice were significantly less pronounced than those observed in control in seven of nine tested conditions (P < 0.04). N-acetyl-l-cysteine (NAC), rescued alternans in myocytes that were previously exposed to an oxidizing agent (P < 0.001). CGP, an antagonist of the mitochondrial Na+-Ca2+ exchanger, had the most severe effect on AR. Exposure to cyclosporin A, a blocker of the mitochondrial permeability transition pore reduced CGP-induced alternans (P < 0.0001). The major findings of this study are that impairment of mitochondrial Ca2+ cycling and energy production leads to a higher amplitude of alternans in both control and SERCA2a-upregulated mice, but changes in SERCA2a-upregulated mice are less severe, indicating that SERCA2a mice are more capable of sustaining electrical stability during stress. This suggests a relationship between sarcoplasmic Ca2+ content and mitochondrial dysfunction during alternans, which may potentially help to understand changes in Ca2+ signaling in myocytes from diseased

Houttuynia cordata polysaccharides ameliorate pneumonia severity and intestinal injury in mice with influenza virus infection.

PubMed

Zhu, Haiyan; Lu, Xiaoxiao; Ling, Lijun; Li, Hong; Ou, Yingye; Shi, Xunlong; Lu, Yan; Zhang, Yunyi; Chen, Daofeng

2018-05-23

Hottuynia cordata is an important traditional Chinese medicine for the treatment of respiratory diseases including bacterial and viral infections. Polysaccharides isolated from Houttuynia cordata (HCP), as its main ingredients, have been demonstrated to ameliorate the LPS-induced acute lung injury in mice. The study aimed to determine the protective effects of HCP on multiple organ injury in influenza A virus (IAV) H1N1 infected mice and its primary mechanisms in anti-inflammation and immune regulation. Mice were inoculated with IAV H1N1 and then treated with 20 or 40 mg/kg/d of HCP for survival test and acute lung-gut injury test. The treatment with HCP resulted in an increase in the survival rate of H1N1 infected mice and the protection from lung and intestine injury, accompanied with the reduced virus replication. HCP markedly decreased the concentration of pulmonary proinflammatory cytokines/chemokines and the number of intestinal goblet cells, and strengthened the intestinal physical and immune barrier, according to the increase of sIgA and tight junction protein (ZO-1) in intestine. At the same time, the inhibition of inflammation in lung and gut was related to the suppressing of the expression of TLR4 and p-NFκB p65 in lung. These results indicated that HCP ameliorated lung and intestine injury induced by IAV attack. The mechanisms were associated with inhibition of inflammation, protection of intestinal barrier and regulation of mucosal immunity, which may be related to the regulation of gut-lung axis. As an alternative medicine, HCP may have clinical potential to treat IAV infection in human beings. Copyright © 2018 Elsevier B.V. All rights reserved.

Salsalate and adiponectin ameliorate hepatic steatosis by inhibition of the hepatokine fetuin-A.

PubMed

Jung, Tae Woo; Youn, Byung-Soo; Choi, Hae Yoon; Lee, So Young; Hong, Ho Cheol; Yang, Sae Jeong; Yoo, Hye Jin; Kim, Baek-Hui; Baik, Sei Hyun; Choi, Kyung Mook

2013-10-01

Fetuin-A was recently identified as a novel hepatokine which is associated with obesity, insulin resistance and non-alcoholic fatty liver disease. Salsalate, a prodrug of salicylate with an anti-inflammatory effect and lower side effect profile, significantly lowers glucose and triglyceride levels, and increased adiponectin concentrations in randomized clinical trials. In this study, we examined the effects and regulatory mechanisms of salsalate and full length-adiponectin (fAd) on fetuin-A expression, steatosis and lipid metabolism in palmitate-treated HepG2 cells. Incubation of hepatocytes with palmitate significantly increased fetuin-A and SREBP-1c expression which lead to steatosis and knock-down of fetuin-A by siRNA restored these changes. Salsalate significantly down-regulated palmitate-induced fetuin-A mRNA expression and secretion in a dose- and time-dependent manner. Inhibition of palmitate-induced fetuin-A by salsalate was mediated by AMPK-mediated reduction of NFκB activity, which was blocked by AMPK siRNA or an inhibitor of AMPK. Salsalate attenuated the excessive steatosis by palmitate through SREBP-1c regulation in hepatocytes. Furthermore, fAd also showed suppression of palmitate-induced fetuin-A through the AMPK pathway and improvement of steatosis accompanied by restoration of SREBP-1c, PAPR-α and CD36. In preliminary in vivo experiments, salsalate treatment inhibited high fat diet (HFD)-induced steatosis as well as fetuin-A mRNA and protein expression in SD rats. In conclusion, salsalate and fAd improved palmitate-induced steatosis and impairment of lipid metabolism in hepatocytes via fetuin-A inhibition through the AMPK-NFκB pathway. Copyright © 2013 Elsevier Inc. All rights reserved.

Inhibition of Pyruvate Dehydrogenase Kinase 2 Protects Against Hepatic Steatosis Through Modulation of Tricarboxylic Acid Cycle Anaplerosis and Ketogenesis.

PubMed

Go, Younghoon; Jeong, Ji Yun; Jeoung, Nam Ho; Jeon, Jae-Han; Park, Bo-Yoon; Kang, Hyeon-Ji; Ha, Chae-Myeong; Choi, Young-Keun; Lee, Sun Joo; Ham, Hye Jin; Kim, Byung-Gyu; Park, Keun-Gyu; Park, So Young; Lee, Chul-Ho; Choi, Cheol Soo; Park, Tae-Sik; Lee, W N Paul; Harris, Robert A; Lee, In-Kyu

2016-10-01

Hepatic steatosis is associated with increased insulin resistance and tricarboxylic acid (TCA) cycle flux, but decreased ketogenesis and pyruvate dehydrogenase complex (PDC) flux. This study examined whether hepatic PDC activation by inhibition of pyruvate dehydrogenase kinase 2 (PDK2) ameliorates these metabolic abnormalities. Wild-type mice fed a high-fat diet exhibited hepatic steatosis, insulin resistance, and increased levels of pyruvate, TCA cycle intermediates, and malonyl-CoA but reduced ketogenesis and PDC activity due to PDK2 induction. Hepatic PDC activation by PDK2 inhibition attenuated hepatic steatosis, improved hepatic insulin sensitivity, reduced hepatic glucose production, increased capacity for β-oxidation and ketogenesis, and decreased the capacity for lipogenesis. These results were attributed to altered enzymatic capacities and a reduction in TCA anaplerosis that limited the availability of oxaloacetate for the TCA cycle, which promoted ketogenesis. The current study reports that increasing hepatic PDC activity by inhibition of PDK2 ameliorates hepatic steatosis and insulin sensitivity by regulating TCA cycle anaplerosis and ketogenesis. The findings suggest PDK2 is a potential therapeutic target for nonalcoholic fatty liver disease. © 2016 by the American Diabetes Association.

Recurrent Moderate Hypoglycemia Suppresses Brain-Derived Neurotrophic Factor Expression in the Prefrontal Cortex and Impairs Sensorimotor Gating in the Post-Hypoglycemia Period in Young Rats

PubMed Central

Rao, Raghavendra; Ennis, Kathleen; Mitchell, Eugena P.; Tran, Phu V.; Gewirtz, Jonathan C.

2016-01-01

Recurrent hypoglycemia is common in infants and children. In developing rat models, recurrent moderate hypoglycemia leads to neuronal injury in the medial prefrontal cortex. To understand the effects beyond neuronal injury, three-week-old male rats were subjected to five episodes of moderate hypoglycemia (blood glucose concentration, approximately 30 mg/dl for 90 min) once daily from postnatal day 24 to 28. Neuronal injury was determined using Fluoro-jade B histochemistry on postnatal day 29. The effects on brain-derived neurotrophic factor (BDNF) and its cognate receptor, tyrosine kinase B (TrkB) expression, which is critical for prefrontal cortex development, were determined on postnatal day 29 and at adulthood. The effects on prefrontal cortex-mediated function were determined by assessing prepulse inhibition of the acoustic startle reflex on postnatal day 29 and two weeks later, and by testing for fear-potentiated startle at adulthood. Recurrent hypoglycemia led to neuronal injury confined primarily to the medial prefrontal cortex. BDNF and TrkB expression in the prefrontal cortex was suppressed on postnatal day 29 and was accompanied by lower prepulse inhibition, suggesting impaired sensorimotor gating. Following the cessation of recurrent hypoglycemia, prepulse inhibition had recovered at two weeks. BDNF/TrkB expression in the prefrontal cortex had normalized and fear-potentiated startle was intact at adulthood. Recurrent moderate hypoglycemia during development has significant adverse effects on the prefrontal cortex in the post-hypoglycemia period. PMID:26820887

Walnut phenolic extract inhibits nuclear factor kappaB signaling in intestinal epithelial cells, and ameliorates experimental colitis and colitis-associated colon cancer in mice.

PubMed

Koh, Seong-Joon; Choi, Youn-I; Kim, Yuri; Kim, Yoo-Sun; Choi, Sang Woon; Kim, Ji Won; Kim, Byeong Gwan; Lee, Kook Lae

2018-05-09

Walnuts (Juglans regia) are known to have anti-cancer and immunomodulatory effects. However, little information is available on the effects of walnut phenolic extract (WPE) on intestinal inflammation and colitis-associated colon cancer. COLO205 cells were pretreated with WPE and then stimulated with tumor necrosis factor (TNF)-α. In the acute colitis model, wild type mice (C57BL/6) were administered 4% dextran sulfate sodium (DSS) for 5 days. In the chronic colitis model, interleukin (IL)-10 -/- mice were administered with either the vehicle or WPE (20 mg/kg) by oral gavage daily for 2 weeks. In an inflammation-associated tumor model, wild type mice were administered a single intraperitoneal injection of azoxymethane followed by three cycles of 2% DSS for 5 days and 2 weeks of free water consumption. WPE significantly inhibited IL-8 and IL-1α expression in COLO205 cells. WPE attenuated both the TNF-α-induced IκB phosphorylation/degradation and NF-κB DNA binding activity. The administration of oral WPE significantly reduced the severity of colitis in both acute and chronic colitis models, including the IL-10 -/- mice. In immunohistochemical staining, WPE attenuated NF-κB signaling in the colons of both colitis models. Finally, WPE also significantly reduced tumor development in a murine model of colitis-associated colon cancer (CAC). WPE ameliorates acute and chronic colitis and CAC in mice, suggesting that WPE may have potentials for the treatment of inflammatory bowel disease.

Inhibition of integrin-linked kinase blocks podocyte epithelial-mesenchymal transition and ameliorates proteinuria.

PubMed

Kang, Young Sun; Li, Yingjian; Dai, Chunsun; Kiss, Lawrence P; Wu, Chuanyue; Liu, Youhua

2010-08-01

Proteinuria is a primary clinical symptom of a large number of glomerular diseases that progress to end-stage renal failure. Podocyte dysfunctions play a fundamental role in defective glomerular filtration in many common forms of proteinuric kidney disorders. Since binding of these cells to the basement membrane is mediated by integrins, we determined the role of integrin-linked kinase (ILK) in podocyte dysfunction and proteinuria. ILK expression was induced in mouse podocytes by various injurious stimuli known to cause proteinuria including TGF-beta1, adriamycin, puromycin, and high ambient glucose. Podocyte ILK was also found to be upregulated in human proteinuric glomerular diseases. Ectopic expression of ILK in podocytes decreased levels of the epithelial markers nephrin and ZO-1, induced mesenchymal markers such as desmin, fibronectin, matrix metalloproteinase-9 (MMP-9), and alpha-smooth muscle actin (alpha-SMA), promoted cell migration, and increased the paracellular albumin flux across podocyte monolayers. ILK also induced Snail, a key transcription factor mediating epithelial-mesenchymal transition (EMT). Blockade of ILK activity with a highly selective small molecule inhibitor reduced Snail induction and preserved podocyte phenotypes following TGF-beta1 or adriamycin stimulation. In vivo, this ILK inhibitor ameliorated albuminuria, repressed glomerular induction of MMP-9 and alpha-SMA, and preserved nephrin expression in murine adriamycin nephropathy. Our results show that upregulation of ILK is a convergent pathway leading to podocyte EMT, migration, and dysfunction. ILK may be an attractive target for therapeutic intervention of proteinuric kidney diseases.

Plumbagin ameliorates memory dysfunction in streptozotocin induced Alzheimer's disease via activation of Nrf2/ARE pathway and inhibition of β-secretase.

PubMed

Nakhate, Kartik T; Bharne, Ashish P; Verma, Vinay Sagar; Aru, Deepali N; Kokare, Dadasaheb M

2018-05-01

Although plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) protects against cerebral ischemia and spinal cord injury-induced oxidative stress and inflammation by activating the nuclear factor-erythroid 2-related factor-2 /antioxidant response element (Nrf2/ARE) pathway, its role in the amelioration of neurodegenerative diseases remains unexplored. In the present study, we investigated the effect of plumbagin on Alzheimer's disease (AD)-like condition in mice. The animals were treated intracerebroventricularly with streptozotocin (STZ; 3 mg/kg) twice, on day 1 and 3, to induce AD-like condition, and the symptoms were evaluated after 14 days. While the loss of learning and memory performance was evident in the mice subjected to Morris water maze (MWM), there was a striking increase in the population of astrocytes labelled with glial fibrillary acidic protein (GFAP) in the hippocampus. Daily intraperitoneal (i.p.) treatment with plumbagin (0.5 and 1 mg/kg), starting from 1 h prior to first dose of STZ, significantly prevented the cognitive deficits in MWM. On the other hand, administration of Nrf2/ARE pathway inhibitor, trigonelline (10 and 15 mg/kg, i.p.) enhanced the effects of STZ. Pre-treatment with subeffective dose of trigonelline (5 mg/kg) significantly attenuated the effects of plumbagin in MWM. While plumbagin prevented the STZ induced GFAP expression, this effect of plumbagin was attenuated by trigonelline. Moreover, the in silico docking study revealed potent inhibitory effect of plumbagin on β-secretase enzyme. The results of the present study suggest that plumbagin improves cognitive function in STZ induced mouse model of AD possibly via Nrf2/ARE mediated suppression of astrogliosis and inhibition of β-secretase enzyme. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Adverse postresuscitation myocardial effects elicited by buffer-induced alkalemia ameliorated by NHE-1 inhibition in a rat model of ventricular fibrillation.

PubMed

Lamoureux, Lorissa; Radhakrishnan, Jeejabai; Mason, Thomas G; Kraut, Jeffrey A; Gazmuri, Raúl J

2016-11-01

Major myocardial abnormalities occur during cardiac arrest and resuscitation including intracellular acidosis-partly caused by CO 2 accumulation-and activation of the Na + -H + exchanger isoform-1 (NHE-1). We hypothesized that a favorable interaction may result from NHE-1 inhibition during cardiac resuscitation followed by administration of a CO 2 -consuming buffer upon return of spontaneous circulation (ROSC). Ventricular fibrillation was electrically induced in 24 male rats and left untreated for 8 min followed by defibrillation after 8 min of cardiopulmonary resuscitation (CPR). Rats were randomized 1:1:1 to the NHE-1 inhibitor zoniporide or vehicle during CPR and disodium carbonate/sodium bicarbonate buffer or normal saline (30 ml/kg) after ROSC. Survival at 240 min declined from 100% with Zoniporide/Saline to 50% with Zoniporide/Buffer and 25% with Vehicle/Buffer (P = 0.004), explained by worsening postresuscitation myocardial dysfunction. Marked alkalemia occurred after buffer administration along with lactatemia that was maximal after Vehicle/Buffer, attenuated by Zoniporide/Buffer, and minimal with Zoniporide/Saline [13.3 ± 4.8 (SD), 9.2 ± 4.6, and 2.7 ± 1.0 mmol/l; P ≤ 0.001]. We attributed the intense postresuscitation lactatemia to enhanced glycolysis consequent to severe buffer-induced alkalemia transmitted intracellularly by an active NHE-1. We attributed the worsened postresuscitation myocardial dysfunction also to severe alkalemia intensifying Na + entry via NHE-1 with consequent Ca 2+ overload injuring mitochondria, evidenced by increased plasma cytochrome c Both buffer-induced effects were ameliorated by zoniporide. Accordingly, buffer-induced alkalemia after ROSC worsened myocardial function and survival, likely through enhancing NHE-1 activity. Zoniporide attenuated these effects and uncovered a complex postresuscitation acid-base physiology whereby blood pH drives NHE-1 activity and compromises mitochondrial function and integrity along

Xanthine oxidase inhibiting effects of noni (Morinda citrifolia) fruit juice.

PubMed

Palu, Afa; Deng, Shixin; West, Brett; Jensen, Jarakae

2009-12-01

Morinda citrifolia L. (noni), family Rubiaceae, has been used in Polynesia for over 2000 years for its reputed health benefits, one of which is its therapeutic effects on gout (langa e hokotanga hui). However, its healing mechanism has not been elucidated. This study showed that in an in vitro bioassay that Tahitian Noni Juice (TNJ) inhibited xanthine oxidase (XO) concentration dependently. Concentrations of 1, 5 and 10 mg/mL of TNJ inhibited XO by 11%, 113% and 148%, respectively, with an IC50 of 3.8 mg compared with an IC50 of 2.4 microm for allopurinol. Noni fruit juice concentrate (NFJC) also inhibited XO concentration dependently. Concentrations of 1 and 5 mg/mL NFJC inhibited XO in vitro by 184% and 159%, respectively. A 0.1 mg/mL methanol extract (NFJME) from the fractionation of noni fruit puree inhibited XO by 64%. It was elucidated that the noni fruit juice inhibitory effect on XO enzymes is the mechanism by which noni ameliorates gout and gout-like diseases. Further, the results also support the traditional usage of noni in the treatment of gout. Copyright (c) 2009 John Wiley & Sons, Ltd.

Sacubitril and valsartan protect from experimental myocardial infarction by ameliorating oxidative damage in Wistar rats.

PubMed

Imran, Mohd; Hassan, Md Quamrul; Akhtar, Md Sayeed; Rahman, Obaid; Akhtar, M; Najmi, Abul Kalam

2018-03-29

Sacubitril (SAC), a neprilysin inhibitor prevent degradation of neprilysin and activate cGMP signaling pathways leading to rise in blood volume concurrent to blood pressure by means of vasoactive peptides, adrenomedullin, and bradykinin. The aim of this study was to evaluate the anti-ischemic effects of SAC through inhibiting neprilysin in isoproterenol (ISO) induced myocardial infarction (MI) in Wistar albino rats. ISO (85 mg/kg) was injected subcutaneously at the end of 14 days pre-treatment with SAC and valsartan (VAL). Biochemical investigation revealed that SAC along with VAL significantly prevented the antioxidant enzymes (SOD, Catalase, GR, GPx, GST, and GSH) degradation and malondialdehyde (MDA) induced by ISO intoxication in Wistar rats. Along with this, cardiac biomarkers (LDH, CK-MB, ALT, AST, and ALP) were also significantly ameliorated by SACand VAL in ISO-treated rats. Concurrently, decreased infarction area (IA)and marked reduction in myofibril damage by SACand VAL further supported its protective benefits in MI. Taken together, the results suggest that inhibition of enzyme neprilysin alleviated the ISO induces myocardial damage mediated by its strong antioxidant potential.

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

Agmatine Ameliorates High Glucose-Induced Neuronal Cell Senescence by Regulating the p21 and p53 Signaling.

PubMed

Song, Juhyun; Lee, Byeori; Kang, Somang; Oh, Yumi; Kim, Eosu; Kim, Chul-Hoon; Song, Ho-Taek; Lee, Jong Eun

2016-02-01

Neuronal senescence caused by diabetic neuropathy is considered a common complication of diabetes mellitus. Neuronal senescence leads to the secretion of pro-inflammatory cytokines, the production of reactive oxygen species, and the alteration of cellular homeostasis. Agmatine, which is biosynthesized by arginine decarboxylation, has been reported in previous in vitro to exert a protective effect against various stresses. In present study, agmatine attenuated the cell death and the expression of pro-inflammatory cytokines such as IL-6, TNF-alpha and CCL2 in high glucose in vitro conditions. Moreover, the senescence associated-β-galatosidase's activity in high glucose exposed neuronal cells was reduced by agmatine. Increased p21 and reduced p53 in high glucose conditioned cells were changed by agmatine. Ultimately, agmatine inhibits the neuronal cell senescence through the activation of p53 and the inhibition of p21. Here, we propose that agmatine may ameliorate neuronal cell senescence in hyperglycemia.

Direct renin inhibitor ameliorates insulin resistance by improving insulin signaling and oxidative stress in the skeletal muscle from post-infarct heart failure in mice.

PubMed

Fukushima, Arata; Kinugawa, Shintaro; Takada, Shingo; Matsumoto, Junichi; Furihata, Takaaki; Mizushima, Wataru; Tsuda, Masaya; Yokota, Takashi; Matsushima, Shouji; Okita, Koichi; Tsutsui, Hiroyuki

2016-05-15

Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI+Aliskiren, n=11). After 4 weeks, MI mice showed left ventricular dilation and dysfunction, which were not affected by aliskiren. The percent decrease of blood glucose after insulin load was significantly smaller in MI than in Sham (14±5% vs. 36±2%), and was ameliorated in MI+Aliskiren (34±5%) mice. Insulin-stimulated serine-phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle of MI compared to Sham by 57% and 69%, and both changes were ameliorated in the MI+Aliskiren group (91% and 94%). Aliskiren administration in MI mice significantly inhibited plasma renin activity and angiotensin II (Ang II) levels. Moreover, (pro)renin receptor expression and local Ang II production were upregulated in skeletal muscle from MI and were attenuated in MI+Aliskiren mice, in tandem with a decrease in superoxide production and NAD(P)H oxidase activities. In conclusion, aliskiren ameliorated insulin resistance in HF by improving insulin signaling in the skeletal muscle, at least partly by inhibiting systemic and (pro)renin receptor-mediated local RAS activation, and subsequent NAD(P)H oxidase-induced oxidative stress. Copyright © 2016 Elsevier B.V. All rights reserved.

27 CFR 24.178 - Amelioration.

Code of Federal Regulations, 2011 CFR

2011-04-01

... is calculated as tartaric acid for grapes, malic acid for apples, and citric acid for other fruit... natural wine from juice having a fixed acid level exceeding 5.0 grams per liter, the winemaker may adjust the fixed acid level by adding ameliorating material (water, sugar, or a combination of both) before...

27 CFR 24.178 - Amelioration.

Code of Federal Regulations, 2010 CFR

2010-04-01

... is calculated as tartaric acid for grapes, malic acid for apples, and citric acid for other fruit... natural wine from juice having a fixed acid level exceeding 5.0 grams per liter, the winemaker may adjust the fixed acid level by adding ameliorating material (water, sugar, or a combination of both) before...

Dual inhibition of acetylcholinesterase and butyrylcholinesterase enzymes by allicin

PubMed Central

Kumar, Suresh

2015-01-01

Objectives: The brain of mammals contains two major form of cholinesterase enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The dual inhibition of these enzymes is considered as a promising strategy for the treatment of neurological disorder such as Alzheimer's disease (AD), senile dementia, ataxia, and myasthenia gravis. The present study was undertaken to explore the anticholinesterase inhibition property of allicin. Materials and Methods: An assessment of cholinesterase inhibition was carried out by Ellman's assay. Results: The present study demonstrates allicin, a major ingredient of crushed garlic (Allium sativum L.) inhibited both AChE and BuChE enzymes in a concentration-dependent manner. For allicin, the IC50 concentration was 0.01 mg/mL (61.62 μM) for AChE and 0.05 ± 0.018 mg/mL (308.12 μM) for BuChE enzymes. Conclusions: Allicin shows a potential to ameliorate the decline of cognitive function and memory loss associated with AD by inhibiting cholinesterase enzymes and upregulate the levels of acetylcholine (ACh) in the brain. It can be used as a new lead to target AChE and BuChE to upregulate the level of ACh which will be useful in alleviating the symptoms associated with AD. PMID:26288480

Wistar-Kyoto rats as an animal model of anxiety vulnerability: support for a hypervigilance hypothesis.

PubMed

McAuley, J D; Stewart, A L; Webber, E S; Cromwell, H C; Servatius, R J; Pang, K C H

2009-12-01

Inbred Wistar-Kyoto (WKY) rats have been proposed as a model of anxiety vulnerability as they display behavioral inhibition and a constellation of learning and reactivity abnormalities relative to outbred Sprague-Dawley (SD) rats. Together, the behaviors of the WKY rat suggest a hypervigilant state that may contribute to its anxiety vulnerability. To test this hypothesis, open-field behavior, acoustic startle, pre-pulse inhibition and timing behavior were assessed in WKY and Sprague-Dawley (SD) rats. Timing behavior was evaluated using a modified version of the peak-interval timing procedure. Training and testing of timing first occurred without audio-visual (AV) interference. Following this initial test, AV interference was included on some trials. Overall, WKY rats took much longer to leave the center of the arena, made fewer line crossings, and reared less, than did SD rats. WKY rats showed much greater startle responses to acoustic stimuli and significantly greater pre-pulse inhibition than did the SD rats. During timing conditions without AV interference, timing accuracy for both strains was similar; peak times for WKY and SD rats were not different. During interference conditions, however, the timing behavior of the two strains was very different. Whereas peak times for SD rats were similar between non-interference and interference conditions, peak times for WKY rats were shorter and response rates higher in interference conditions than in non-interference conditions. The enhanced acoustic startle response, greater prepulse inhibition and altered timing behavior with audio-visual interference supports a characterization of WKY strain as hypervigilant and provides further evidence for the use of the WKY strain as a model of anxiety vulnerability.

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.

Neuroprotective effect and mechanism of daucosterol palmitate in ameliorating learning and memory impairment in a rat model of Alzheimer's disease.

PubMed

Ji, Zhi-Hong; Xu, Zhong-Qi; Zhao, Hong; Yu, Xin-Yu

2017-03-01

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory decline and cognitive impairment. Amyloid beta (Aβ) has been proposed as the causative role for the pathogenesis of AD. Accumulating evidence demonstrates that Aβ neurotoxicity is mediated by glutamate excitotoxicity. Daucosterol palmitate (DSP), a plant steroid with anti-glutamate excitotoxicity effect, was isolated from the anti-aging traditional Chinese medicinal herb Alpinia oxyphylla Miq. in our previous study. Based on the anti-glutamate excitotoxicity effect of DSP, in this study we investigated potential benefit and mechanism of DSP in ameliorating learning and memory impairment in AD model rats. Results from this study showed that DSP administration effectively ameliorated Aβ-induced learning and memory impairment in rats, markedly inhibited Aβ-induced hippocampal ROS production, effectively prevented Aβ-induced hippocampal neuronal damage and significantly restored hippocampal synaptophysin expression level. This study suggests that DSP may be a potential candidate for development as a therapeutic agent for AD cognitive decline. Copyright © 2017 Elsevier Inc. All rights reserved.

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

2017-05-15

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. Copyright © 2017 Elsevier Inc. All rights reserved.

Cyanidin-3-glucoside ameliorates ethanol neurotoxicity in the developing brain.

PubMed

Ke, Zunji; Liu, Ying; Wang, Xin; Fan, Zhiqin; Chen, Gang; Xu, Mei; Bower, Kimberley A; Frank, Jacqueline A; Ou, Xiaoming; Shi, Xianglin; Luo, Jia

2011-10-01

Ethanol exposure induces neurodegeneration in the developing central nervous system (CNS). Fetal alcohol spectrum disorders (FASD) are caused by ethanol exposure during pregnancy and are the most common nonhereditary cause of mental retardation. It is important to identify agents that provide neuroprotection against ethanol neurotoxicity. Multiple mechanisms have been proposed for ethanol-induced neurodegeneration, and oxidative stress is one of the most important mechanisms. Recent evidence indicates that glycogen synthase kinase 3β (GSK3β) is a potential mediator of ethanol-mediated neuronal death. Cyanidin-3-glucoside (C3G), a member of the anthocyanin family, is a potent natural antioxidant. Our previous study suggested that C3G inhibited GSK3β activity in neurons. Using a third trimester equivalent mouse model of ethanol exposure, we tested the hypothesis that C3G can ameliorate ethanol-induced neuronal death in the developing brain. Intraperitoneal injection of C3G reduced ethanol-meditated caspase-3 activation, neurodegeneration, and microglial activation in the cerebral cortex of 7-day-old mice. C3G blocked ethanol-mediated GSK3β activation by inducing phosphorylation at serine 9 while reducing the phosphorylation at tyrosine 216. C3G also inhibited ethanol-stimulated expression of malondialdehyde (MDA) and p47phox, indicating that C3G alleviated ethanol-induced oxidative stress. These results provide important insight into the therapeutic potential of C3G. Copyright © 2011 Wiley-Liss, Inc.

Cyanidin-3-Glucoside Ameliorates Ethanol Neurotoxicity in the Developing Brain

PubMed Central

Ke, Zunji; Liu, Ying; Wang, Xin; Fan, Zhiqin; Chen, Gang; Xu, Mei; Bower, Kimberley A.; Frank, Jacqueline A.; Ou, Xiaoming; Shi, Xianglin; Luo, Jia

2011-01-01

Ethanol exposure induces neurodegeneration in the developing central nervous system (CNS). Fetal Alcohol Spectrum Disorders (FASD) are caused by ethanol exposure during pregnancy and are the most common nonhereditary cause of mental retardation. It is important to identify agents that provide neuroprotection against ethanol neurotoxicity. Multiple mechanisms have been proposed for ethanol-induced neurodegeneration, and oxidative stress is one of the most important mechanisms. Recent evidence indicates that glycogen synthase kinase 3β (GSK3β) is a potential mediator of ethanol-mediated neuronal death (Luo, 2009). Cyanidin-3-glucoside (C3G), a member of the anthocyanin family, is a potent natural antioxidant. Our previous study suggested that C3G inhibited GSK3β activity in neurons (Chen et al., 2009). Using a third trimester equivalent mouse model of ethanol exposure, we tested the hypothesis that C3G can ameliorate ethanol-induced neuronal death in the developing brain. Intraperitoneal injection of C3G reduced ethanol-meditated caspase-3 activation, neurodegeneration and microglial activation in the cerebral cortex of seven-day-old mice. C3G blocked ethanol-mediated GSK3β activation by inducing the phosphorylation at serine 9 while reducing the phosphorylation at tyrosine 216. C3G also inhibited ethanol-stimulated expression of malondialdehyde (MDA) and p47phox, indicating that C3G alleviated ethanol-induced oxidative stress. These results provide important insight into the therapeutic potential of C3G. PMID:21671257

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

PubMed Central

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

2009-01-01

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

IL-10 gene transfer upregulates arcuate POMC and ameliorates hyperphagia, obesity and diabetes by substituting for leptin.

PubMed

Nakata, M; Yamamoto, S; Okada, T; Gantulga, D; Okano, H; Ozawa, K; Yada, T

2016-03-01

Obesity and metabolic syndrome are the major risk factors for cardiovascular disease. Obesity is caused by increased food intake and/or decreased energy expenditure. Leptin potently inhibits food intake and promotes energy expenditure. These effects of leptin involve the activation of proopiomelanocortin (POMC) neurons in the hypothalamus arcuate nucleus (ARC). Disruption of leptin signaling in POMC neuron is considered one of the major causes for obesity. The present study aimed to examine whether overexpression of interleukin-10 (IL-10) could substitute for the leptin action and ameliorate obesity in leptin-deficient Lep(ob/ob) mice. Adeno-associated virus (AAV) expressing murine IL-10 (AAV-mIL-10) was injected into the skeletal muscle to overexpress IL-10 in mice. These mice were subsequently subjected to analysis of body weight, food intake, glucose metabolism and underlying mechanisms. In Lep(ob/ob) mice, AAV-IL-10 ameliorated hyperphagia, obesity, glucose intolerance and insulin resistance, as well as attenuated tumor necrosis factor-α expression. The IL-10 treatment also improved glucose-induced insulin release. Furthermore, IL-10 treatment increased POMC mRNA expression in ARC and phosphorylation of signal transducer and activator of transcription-3 (STAT3) in ARC and white adipose tissue (WAT). In neuron-specific STAT3-null mice that exhibited obesity and hyperphagia, AAV-mIL-10 administration failed to affect food intake, body weight and phosphorylation of STAT3 in WAT. These results demonstrate that peripheral overexpression of IL-10 induces STAT3 phosphorylation in ARC POMC neurons, and thereby ameliorates hyperphagia and obesity caused by leptin deficiency. IL-10 gene transfer may provide an effective approach for preventing progression of metabolic syndrome due to leptin resistance.

GM-CSF ameliorates microvascular barrier integrity via pericyte-derived Ang-1 in wound healing.

PubMed

Yan, Min; Hu, Yange; Yao, Min; Bao, Shisan; Fang, Yong

2017-11-01

Skin wound healing involves complex coordinated interactions of cells, tissues, and mediators. Maintaining microvascular barrier integrity is one of the key events for endothelial homeostasis during wound healing. Vasodilation is observed after vasoconstriction, which causes blood vessels to become porous, facilitates leukocyte infiltration and aids angiogenesis at the wound-area, postinjury. Eventually, vessel integrity has to be reestablished for vascular maturation. Numerous studies have found that granulocyte macrophage colony-stimulating factor (GM-CSF) accelerates wound healing by inducing recruitment of repair cells into the injury area and releases of cytokines. However, whether GM-CSF is involving in the maintaining of microvascular barrier integrity and the underlying mechanism remain still unclear. Aim of this study was to investigate the effects of GM-CSF on modulation of microvascular permeability in wound healing and underlying mechanisms. Wound closure and microvascular leakage was investigated using a full-thickness skin wound mouse model after GM-CSF intervention. The endothelial permeability was measured by Evans blue assay in vivo and in vitro endothelium/pericyte co-culture system using a FITC-Dextran permeability assay. To identify the source of angiopoietin-1 (Ang-1), double staining is used in vivo and ELISA and qPCR are used in vitro. To determine the specific effect of Ang-1 on GM-CSF maintaining microvascular stabilization, Ang-1 siRNA was applied to inhibit Ang-1 production in vivo and in vitro. Wound closure was significantly accelerated and microvascular leakage was ameliorated after GM-CSF treatment in mouse wound sites. GM-CSF decreased endothelial permeability through tightening endothelial junctions and increased Ang-1 protein level that was derived by perictye. Furthermore, applications of siRNAAng-1 inhibited GM-CSF mediated protection of microvascular barrier integrity both in vivo and in vitro. Our data indicate that GM

Pirfenidone ameliorates murine chronic GVHD through inhibition of macrophage infiltration and TGF-β production

PubMed Central

Du, Jing; Paz, Katelyn; Flynn, Ryan; Vulic, Ante; Robinson, Tara M.; Lineburg, Katie E.; Alexander, Kylie A.; Meng, Jingjing; Roy, Sabita; Panoskaltsis-Mortari, Angela; Loschi, Michael; Hill, Geoffrey R.; Serody, Jonathan S.; Maillard, Ivan; Miklos, David; Koreth, John; Cutler, Corey S.; Antin, Joseph H.; Ritz, Jerome; MacDonald, Kelli P.; Schacker, Timothy W.; Luznik, Leo

2017-01-01

Allogeneic hematopoietic stem cell transplantation is hampered by chronic graft-versus-host disease (cGVHD), resulting in multiorgan fibrosis and diminished function. Fibrosis in lung and skin leads to progressive bronchiolitis obliterans (BO) and scleroderma, respectively, for which new treatments are needed. We evaluated pirfenidone, a Food and Drug Administration (FDA)-approved drug for idiopathic pulmonary fibrosis, for its therapeutic effect in cGVHD mouse models with distinct pathophysiology. In a full major histocompatibility complex (MHC)-mismatched, multiorgan system model with BO, donor T-cell responses that support pathogenic antibody production are required for cGVHD development. Pirfenidone treatment beginning one month post-transplant restored pulmonary function and reversed lung fibrosis, which was associated with reduced macrophage infiltration and transforming growth factor-β production. Pirfenidone dampened splenic germinal center B-cell and T-follicular helper cell frequencies that collaborate to produce antibody. In both a minor histocompatibility antigen–mismatched as well as a MHC-haploidentical model of sclerodermatous cGVHD, pirfenidone significantly reduced macrophages in the skin, although clinical improvement of scleroderma was only seen in one model. In vitro chemotaxis assays demonstrated that pirfenidone impaired macrophage migration to monocyte chemoattractant protein-1 (MCP-1) as well as IL-17A, which has been linked to cGVHD generation. Taken together, our data suggest that pirfenidone is a potential therapeutic agent to ameliorate fibrosis in cGVHD. PMID:28254742

11β-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice

PubMed Central

Hermanowski-Vosatka, Anne; Balkovec, James M.; Cheng, Kang; Chen, Howard Y.; Hernandez, Melba; Koo, Gloria C.; Le Grand, Cheryl B.; Li, Zhihua; Metzger, Joseph M.; Mundt, Steven S.; Noonan, Heather; Nunes, Christian N.; Olson, Steven H.; Pikounis, Bill; Ren, Ning; Robertson, Nancy; Schaeffer, James M.; Shah, Kashmira; Springer, Martin S.; Strack, Alison M.; Strowski, Matthias; Wu, Kenneth; Wu, TsueiJu; Xiao, Jianying; Zhang, Bei B.; Wright, Samuel D.; Thieringer, Rolf

2005-01-01

The enzyme 11β–hydroxysteroid dehydrogenase (HSD) type 1 converts inactive cortisone into active cortisol in cells, thereby raising the effective glucocorticoid (GC) tone above serum levels. We report that pharmacologic inhibition of 11β-HSD1 has a therapeutic effect in mouse models of metabolic syndrome. Administration of a selective, potent 11β-HSD1 inhibitor lowered body weight, insulin, fasting glucose, triglycerides, and cholesterol in diet-induced obese mice and lowered fasting glucose, insulin, glucagon, triglycerides, and free fatty acids, as well as improved glucose tolerance, in a mouse model of type 2 diabetes. Most importantly, inhibition of 11β-HSD1 slowed plaque progression in a murine model of atherosclerosis, the key clinical sequela of metabolic syndrome. Mice with a targeted deletion of apolipoprotein E exhibited 84% less accumulation of aortic total cholesterol, as well as lower serum cholesterol and triglycerides, when treated with an 11β-HSD1 inhibitor. These data provide the first evidence that pharmacologic inhibition of intracellular GC activation can effectively treat atherosclerosis, the key clinical consequence of metabolic syndrome, in addition to its salutary effect on multiple aspects of the metabolic syndrome itself. PMID:16103409

Ameliorating Effects of Sulfonylurea Drugs on Insulin Resistance in Otsuka Long-Evans Tokushima Fatty Rats

PubMed Central

Park, Jeong-Kwon; Kim, Sang-Pyo

2008-01-01

OLETF (Otsuka Long-Evans Tokushima Fatty) rats are characterized by obesity-related insulin resistance, which is a phenotype of type 2 diabetes. Sulfonylurea drugs or benzoic acid derivatives as inhibitors of the ATP-sensitive potassium (KATP) channel are commercially available to treat diabetes. The present study compared sulfonylurea drugs (glimepiride and gliclazide) with one of benzoic acid derivatives (repaglinide) in regard to their long-term effect on ameliorating insulin sensitivity in OLETF rats. Each drug was dissolved and fed with drinking water from 29 weeks of age. On high glucose loading at 45 weeks of age, response of blood glucose recovery was the greatest in the group treated with glimepiride. On immunohistochemistry analysis for the Kir6.2 subunit of KATP channels, insulin receptor β-subunits, and glucose transporters (GLUT) type 2 and 4 in liver, fat and skeletal muscle tissues, the sulfonylurea drugs (glimepiride and gliclazide) were more effective than repaglinide in recovery from their decreased expressions in OLETF rats. From these results, it seems to be plausible that KATP-channel inhibitors containing sulfonylurea moiety may be much more effective in reducing insulin resistance than those with benzoic acid moiety. In contrast to gliclazide, non-tissue selectivity of glimepiride on KATP channel inhibition may further strengthen an amelioration of insulin sensitivity unless considering other side effects. PMID:20157388

Ameliorating effects of sulfonylurea drugs on insulin resistance in Otsuka long-evans Tokushima Fatty rats.

PubMed

Park, Jeong-Kwon; Kim, Sang-Pyo; Song, Dae-Kyu

2008-02-01

OLETF (Otsuka Long-Evans Tokushima Fatty) rats are characterized by obesity-related insulin resistance, which is a phenotype of type 2 diabetes. Sulfonylurea drugs or benzoic acid derivatives as inhibitors of the ATP-sensitive potassium (K(ATP)) channel are commercially available to treat diabetes. The present study compared sulfonylurea drugs (glimepiride and gliclazide) with one of benzoic acid derivatives (repaglinide) in regard to their long-term effect on ameliorating insulin sensitivity in OLETF rats. Each drug was dissolved and fed with drinking water from 29 weeks of age. On high glucose loading at 45 weeks of age, response of blood glucose recovery was the greatest in the group treated with glimepiride. On immunohistochemistry analysis for the Kir6.2 subunit of K(ATP) channels, insulin receptor beta-subunits, and glucose transporters (GLUT) type 2 and 4 in liver, fat and skeletal muscle tissues, the sulfonylurea drugs (glimepiride and gliclazide) were more effective than repaglinide in recovery from their decreased expressions in OLETF rats. From these results, it seems to be plausible that K(ATP)-channel inhibitors containing sulfonylurea moiety may be much more effective in reducing insulin resistance than those with benzoic acid moiety. In contrast to gliclazide, non-tissue selectivity of glimepiride on K(ATP) channel inhibition may further strengthen an amelioration of insulin sensitivity unless considering other side effects.

Saxagliptin Attenuates Albuminuria by Inhibiting Podocyte Epithelial- to-Mesenchymal Transition via SDF-1α in Diabetic Nephropathy.

PubMed

Chang, Yun-Peng; Sun, Bei; Han, Zhe; Han, Fei; Hu, Shao-Lan; Li, Xiao-Yu; Xue, Mei; Yang, Yang; Chen, Li; Li, Chun-Jun; Chen, Li-Ming

2017-01-01

The dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin has been found to reduce progressive albuminuria, but the exact mechanism of inhibition is unclear. Podocyte epithelial-to-mesenchymal transition (EMT) has emerged as a potential pathway leading to proteinuria in diabetic nephropathy (DN). Stromal cell-derived factor-1α (SDF-1α), one of the substrates of DPP-4, can activate the protein kinase A pathway and subsequently inhibit its downstream effector, transforming growth factor-β1 (TGF-β1), which induces podocyte EMT. Thus, this study was designed to test the hypothesis that saxagliptin reduces progressive albuminuria by preventing podocyte EMT through inhibition of SDF-1α cleavage in DN. The results of a series of assays, including ELISA, western blotting, and immunochemistry/immunofluorescence, showed that saxagliptin treatment obviously ameliorated urinary microalbumin excretion and renal histological changes in high-fat diet/streptozotocin-induced diabetic rats. Furthermore, saxagliptin-treated diabetic rats presented with suppression of DPP-4 activity/protein expression accompanied by restoration of SDF-1α levels, which subsequently hindered NOX2 expression and podocyte EMT. In vitro , we consistently observed that saxagliptin significantly inhibited increased DPP-4 activity/expression, oxidative stress and podocyte EMT. Application of an SDF-1α receptor inhibitor (AMD3100) to cultured podocytes further confirmed the essential role of SDF-1α in podocyte EMT inhibition. In sum, we demonstrated for the first time that saxagliptin treatment plays an essential role in ameliorating progressive DN by preventing podocyte EMT through a SDF-1α-related pathway, suggesting that saxagliptin could offer renoprotection and that SDF-1α might be a potential therapeutic target for DN.

Saxagliptin Attenuates Albuminuria by Inhibiting Podocyte Epithelial- to-Mesenchymal Transition via SDF-1α in Diabetic Nephropathy

PubMed Central

Chang, Yun-peng; Sun, Bei; Han, Zhe; Han, Fei; Hu, Shao-lan; Li, Xiao-yu; Xue, Mei; Yang, Yang; Chen, Li; Li, Chun-jun; Chen, Li-ming

2017-01-01

The dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin has been found to reduce progressive albuminuria, but the exact mechanism of inhibition is unclear. Podocyte epithelial-to-mesenchymal transition (EMT) has emerged as a potential pathway leading to proteinuria in diabetic nephropathy (DN). Stromal cell–derived factor-1α (SDF-1α), one of the substrates of DPP-4, can activate the protein kinase A pathway and subsequently inhibit its downstream effector, transforming growth factor-β1 (TGF-β1), which induces podocyte EMT. Thus, this study was designed to test the hypothesis that saxagliptin reduces progressive albuminuria by preventing podocyte EMT through inhibition of SDF-1α cleavage in DN. The results of a series of assays, including ELISA, western blotting, and immunochemistry/immunofluorescence, showed that saxagliptin treatment obviously ameliorated urinary microalbumin excretion and renal histological changes in high-fat diet/streptozotocin-induced diabetic rats. Furthermore, saxagliptin-treated diabetic rats presented with suppression of DPP-4 activity/protein expression accompanied by restoration of SDF-1α levels, which subsequently hindered NOX2 expression and podocyte EMT. In vitro, we consistently observed that saxagliptin significantly inhibited increased DPP-4 activity/expression, oxidative stress and podocyte EMT. Application of an SDF-1α receptor inhibitor (AMD3100) to cultured podocytes further confirmed the essential role of SDF-1α in podocyte EMT inhibition. In sum, we demonstrated for the first time that saxagliptin treatment plays an essential role in ameliorating progressive DN by preventing podocyte EMT through a SDF-1α-related pathway, suggesting that saxagliptin could offer renoprotection and that SDF-1α might be a potential therapeutic target for DN. PMID:29163166

Biochar from commercially cultivated seaweed for soil amelioration

PubMed Central

Roberts, David A.; Paul, Nicholas A.; Dworjanyn, Symon A.; Bird, Michael I.; de Nys, Rocky

2015-01-01

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. PMID:25856799

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.

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.

Quercetin Inhibits Fibroblast Activation and Kidney Fibrosis Involving the Suppression of Mammalian Target of Rapamycin and β-catenin Signaling

PubMed Central

Ren, Jiafa; Li, Jianzhong; Liu, Xin; Feng, Ye; Gui, Yuan; Yang, Junwei; He, Weichun; Dai, Chunsun

2016-01-01

Quercetin, a flavonoid found in a wide variety of plants and presented in human diet, displays promising potential in preventing kidney fibroblast activation. However, whether quercetin can ameliorate kidney fibrosis in mice with obstructive nephropathy and the underlying mechanisms remain to be further elucidated. In this study, we found that administration of quercetin could largely ameliorate kidney interstitial fibrosis and macrophage accumulation in the kidneys with obstructive nephropathy. MTORC1, mTORC2, β-catenin as well as Smad signaling were activated in the obstructive kidneys, whereas quercetin could markedly reduce their abundance except Smad3 phosphorylation. In cultured NRK-49F cells, quercetin could inhibit α-SMA and fibronectin (FN) expression induced by TGFβ1 treatment. MTORC1, mTORC2, β-catenin and Smad signaling pathways were stimulated by TGFβ1 at a time dependent manner. Similar to those findings in the obstructive kidneys, mTORC1, mTORC2 and β-catenin, but not Smad signaling pathways were remarkably blocked by quercetin treatment. Together, these results suggest that quercetin inhibits fibroblast activation and kidney fibrosis involving a combined inhibition of mTOR and β-catenin signaling transduction, which may act as a therapeutic candidate for patients with chronic kidney diseases. PMID:27052477

Carbachol ameliorates lipopolysaccharide-induced intestinal epithelial tight junction damage by down-regulating NF-κβ and myosin light-chain kinase pathways.

PubMed

Zhang, Ying; Li, Jianguo

2012-11-16

Carbachol is a cholinergic agonist that protects the intestines after trauma or burn injury. The present study determines the beneficial effects of carbachol and the mechanisms by which it ameliorates the lipopolysaccharide (LPS)-induced intestinal barrier breakdown. Rats were injected intraperitoneally with 10 mg/kg LPS. Results showed that the gut barrier permeability was reduced, the ultrastructural disruption of tight junctions (TJs) was prevented, the redistribution of zonula occludens-1 and claudin-2 proteins was partially reversed, and the nuclear factor-kappa beta (NF-κβ) and myosin light-chain kinase (MLCK) activation in the intestinal epithelium were suppressed after carbachol administration in LPS-exposed rats. Pretreatment with the α7 nicotinic acetylcholine receptor (α7nAchR) antagonist α-bungarotoxin blocked the protective action of carbachol. These results suggested that carbachol treatment can protect LPS-induced intestinal barrier dysfunction. Carbachol exerts its beneficial effect on the amelioration of the TJ damage by inhibiting the NF-κβ and MLCK pathways in an α7nAchR-dependent manner. Copyright © 2012 Elsevier Inc. All rights reserved.

Myostatin inhibition prevents diabetes and hyperphagia in a mouse model of lipodystrophy.

PubMed

Guo, Tingqing; Bond, Nichole D; Jou, William; Gavrilova, Oksana; Portas, Jennifer; McPherron, Alexandra C

2012-10-01

Lipodystrophies are characterized by a loss of white adipose tissue, which causes ectopic lipid deposition, peripheral insulin resistance, reduced adipokine levels, and increased food intake (hyperphagia). The growth factor myostatin (MSTN) negatively regulates skeletal muscle growth, and mice with MSTN inhibition have reduced adiposity and improved insulin sensitivity. MSTN inhibition may therefore be efficacious in ameliorating diabetes. To test this hypothesis, we inhibited MSTN signaling in a diabetic model of generalized lipodystrophy to analyze its effects on glucose metabolism separate from effects on adipose mass. A-ZIP/F1 lipodystrophic mice were crossed to mice expressing a dominant-negative MSTN receptor (activin receptor type IIB) in muscle. MSTN inhibition in A-ZIP/F1 mice reduced blood glucose, serum insulin, triglyceride levels, and the rate of triglyceride synthesis, and improved insulin sensitivity. Unexpectedly, hyperphagia was normalized by MSTN inhibition in muscle. Blood glucose and hyperphagia were reduced in double mutants independent of the adipokine leptin. These results show that the effect of MSTN inhibition on insulin sensitivity is not secondary to an effect on adipose mass and that MSTN inhibition may be an effective treatment for diabetes. These results further suggest that muscle may play a heretofore unappreciated role in regulating food intake.

Myostatin Inhibition Prevents Diabetes and Hyperphagia in a Mouse Model of Lipodystrophy

PubMed Central

Guo, Tingqing; Bond, Nichole D.; Jou, William; Gavrilova, Oksana; Portas, Jennifer; McPherron, Alexandra C.

2012-01-01

Lipodystrophies are characterized by a loss of white adipose tissue, which causes ectopic lipid deposition, peripheral insulin resistance, reduced adipokine levels, and increased food intake (hyperphagia). The growth factor myostatin (MSTN) negatively regulates skeletal muscle growth, and mice with MSTN inhibition have reduced adiposity and improved insulin sensitivity. MSTN inhibition may therefore be efficacious in ameliorating diabetes. To test this hypothesis, we inhibited MSTN signaling in a diabetic model of generalized lipodystrophy to analyze its effects on glucose metabolism separate from effects on adipose mass. A-ZIP/F1 lipodystrophic mice were crossed to mice expressing a dominant-negative MSTN receptor (activin receptor type IIB) in muscle. MSTN inhibition in A-ZIP/F1 mice reduced blood glucose, serum insulin, triglyceride levels, and the rate of triglyceride synthesis, and improved insulin sensitivity. Unexpectedly, hyperphagia was normalized by MSTN inhibition in muscle. Blood glucose and hyperphagia were reduced in double mutants independent of the adipokine leptin. These results show that the effect of MSTN inhibition on insulin sensitivity is not secondary to an effect on adipose mass and that MSTN inhibition may be an effective treatment for diabetes. These results further suggest that muscle may play a heretofore unappreciated role in regulating food intake. PMID:22596054

Ganoderma atrum polysaccharide ameliorates anoxia/reoxygenation-mediated oxidative stress and apoptosis in human umbilical vein endothelial cells.

PubMed

Zhang, Yan-Song; Li, Wen-Juan; Zhang, Xian-Yi; Yan, Yu-Xin; Nie, Shao-Ping; Gong, De-Ming; Tang, Xiao-Fang; He, Ming; Xie, Ming-Yong

2017-05-01

Ganoderma atrum polysaccharide (PSG-1), a main polysaccharide from Ganoderma atrum, possesses potent antioxidant capacity and cardiovascular benefits. The aim of this study was to investigate the role of PSG-1 in oxidative stress and apoptosis in human umbilical vein endothelial cells (HUVECs) under anoxia/reoxygenation (A/R) injury conditions. The results showed that exposure of HUVECs to A/R triggered cell death and apoptosis. Administration of PSG-1 significantly inhibited A/R-induced cell death and apoptosis in HUVECs. PSG-1-reduced A/R injury was mediated via mitochondrial apoptotic pathway, as evidenced by elevation of mitochondrial Bcl-2 protein and mitochondrial membrane potential, and attenuation of Bax translocation, cytochrome c release and caspases activation. Furthermore, PSG-1 enhanced the activities of superoxide dismutase, catalase and glutathione peroxidase and glutathione content, and concomitantly attenuated reactive oxygen species generation, lipid peroxidation and glutathione disulfide content. The antioxidant, N-acetyl-l-cysteine, significantly ameliorated all of these endothelial injuries caused by A/R, suggesting that antioxidant activities might play a key role in PSG-1-induced endothelial protection. Taken together, these findings suggested that PSG-1 could be as a promising adjuvant against endothelial dysfunction through ameliorating oxidative stress and apoptosis. Copyright © 2017 Elsevier B.V. All rights reserved.

Neonatal allopregnanolone levels alteration: effects on behavior and role of the hippocampus.

PubMed

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

2014-02-01

Several works have pointed out the importance of the neurosteroid allopregnanolone for the maturation of the central nervous system and for adult behavior. The alteration of neonatal allopregnanolone levels in the first weeks of life alters emotional adult behavior and sensory gating processes. Without ruling out brain structures, some of these behavioral alterations seem to be related to a different functioning of the hippocampus in adult age. We focus here on the different behavioral studies that have revealed the importance of neonatal allopregnanolone levels for the adult response to novel environmental stimuli, anxiety-related behaviors and processing of sensory inputs (prepulse inhibition). An increase in neonatal physiological allopregnanolone levels decreases anxiety and increases novelty responses in adult age, thus affecting the individual response to environmental cues. These effects are also accompanied by a decrease in prepulse inhibition, indicating alterations in sensory gating that have been related to that present in disorders, such as schizophrenia. Moreover, behavioral studies have shown that some of these effects are related to a different functioning of the dorsal hippocampus, as the behavioral effects (decrease in anxiety and locomotion or increase in prepulse inhibition) of intrahippocampal allopregnanolone infusions in adult age are not present in those subjects in whom neonatal allopregnanolone levels were altered. Recent data indicated that this hippocampal involvement may be related to alterations in the expression of gamma-aminobutyric-acid receptors containing α4 and δ subunits, molecular alterations that can persist into adult age and that can, in part, explain the reported behavioral disturbances. Copyright © 2013 Elsevier Ltd. All rights reserved.

27 CFR 24.178 - Amelioration.

Code of Federal Regulations, 2012 CFR

2012-04-01

... natural wine from juice having a fixed acid level exceeding 5.0 grams per liter, the winemaker may adjust... acid level of the juice or wine by 0.1 gram per liter (the fixed acid level of the juice or wine may not be less than 5.0 gram per liter after the addition of ameliorating material). (b) Limitations. (1...

27 CFR 24.178 - Amelioration.

Code of Federal Regulations, 2014 CFR

2014-04-01

... natural wine from juice having a fixed acid level exceeding 5.0 grams per liter, the winemaker may adjust... acid level of the juice or wine by 0.1 gram per liter (the fixed acid level of the juice or wine may not be less than 5.0 gram per liter after the addition of ameliorating material). (b) Limitations. (1...

27 CFR 24.178 - Amelioration.

Code of Federal Regulations, 2013 CFR

2013-04-01

... natural wine from juice having a fixed acid level exceeding 5.0 grams per liter, the winemaker may adjust... acid level of the juice or wine by 0.1 gram per liter (the fixed acid level of the juice or wine may not be less than 5.0 gram per liter after the addition of ameliorating material). (b) Limitations. (1...

Dietary component isorhamnetin is a PPARγ antagonist and ameliorates metabolic disorders induced by diet or leptin deficiency.

PubMed

Zhang, Yu; Gu, Ming; Cai, Wujie; Yu, Lijing; Feng, Li; Zhang, Lu; Zang, Qingqing; Wang, Yahui; Wang, Dongshan; Chen, Hui; Tong, Qingchun; Ji, Guang; Huang, Cheng

2016-01-18

Studies on peroxisome proliferator-activated receptor (PPAR)-γ ligands have been focused on agonists. However, PPARγ activation may induce obesity and nonalcoholic fatty liver disease (NAFLD), one of the most challenging medical conditions. Here, we identified that isorhamnetin, a naturally occurring compound in fruits and vegetables and the metabolite of quercetin, is a novel antagonist of PPARγ. Isorhamnetin treatment inhibited the adipocyte differentiation induced by the PPARγ agonist rosiglitazone, reduced obesity development and ameliorated hepatic steatosis induced by both high-fat diet treatment and leptin deficiency. Our results suggest that dietary supplement of isorhamnetin may be beneficial to prevent obesity and steatosis and PPARγ antagonists may be useful to treat hepatic steatosis.

Hydrogen-rich saline ameliorates the severity of L-arginine-induced acute pancreatitis in rats

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

Chen, Han; Sun, Yan Ping; Li, Yang

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 pancreasmore » 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.« less

Black seed oil ameliorates allergic airway inflammation by inhibiting T-cell proliferation in rats.

PubMed

Shahzad, Muhammad; Yang, Xudong; Raza Asim, M B; Sun, Qingzhu; Han, Yan; Zhang, Fujun; Cao, Yongxiao; Lu, Shemin

2009-02-01

The black seeds, from the Ranunculaceae family, have been traditionally used by various cultures as a natural remedy for several ailments. In this study, we examined the effect of black seed oil as an immunomodulator in a rat model of allergic airway inflammation. Rats sensitized to ovalbumin and challenged intranasally with ovalbumin to induce an allergic inflammatory response were compared to ovalbumin-sensitized, intranasally ovalbumin-exposed rats pretreated with intraperitoneally administered black seed oil and to control rats. The levels of IgE, IgG1 and ova-specific T-cell proliferation in spleen were measured by ELISA. The pro-inflammatory cytokine IL-4, IL-5, IL-6 and TGF-beta1 mRNA expression levels were measured by reverse transcription polymerase chain reaction. The intraperitoneal administration of black seed oil inhibited the Th2 type immune response in rats by preventing inflammatory cell infiltration and pathological lesions in the lungs. It significantly decreased the nitric oxide production in BALF, total serum IgE, IgG1 and OVA-specific IgG1 along with IL-4, IL-5, IL-6 and TGF-beta1 mRNA expression. Black seed oil treatment resulted in decreased T-cell response evident by lesser delayed type hypersensitivity and lower T-cell proliferation in spleen. In conclusion, black seed oil exhibited a significant reduction in all the markers of allergic inflammation mainly by inhibiting the delayed type hypersensitivity and T-cell proliferation. The data suggests that inhibition of T-cell response may be responsible for immunomodulatory effect of black seed oil in the rat model of allergic airway inflammation.

Qi-Dan Fang ameliorates adriamycin-induced nephrotic syndrome rat model by enhancing renal function and inhibiting podocyte injury.

PubMed

Wu, Jun-Biao; Ye, Shu-Fang; Liang, Chun-Ling; Li, Yu-Cui; Yu, Ying-Jia; Lai, Jie-Mei; Lin, Hui; Zheng, Jie; Zhou, Jiu-Yao

2014-02-12

Nephrotic syndrome (NS) is a clinical syndrome with a variety of causes, mainly characterized by heavy proteinuria. Podocyte injury plays a key role in proteinuria, one of the principal means for the control of NS is to prevent podocyte injury. Qi-Dan Fang consists of two of the most extensively applied herbal remedies among Traditional Chinese Medicine (TCM) (Radix Astragali Mongolici and Radix Salviae Miltiorrhizae, with a weight ratio of 5:1) which are specifically used for the treatment of various kidney diseases. In previous studies, we found that Qi-Dan Fang provides improvement to patients with adriamycin-induced nephrotic syndrome by alleviating proteinuria and serum lipid. The aim of this study is to study the efficiency of Qi-Dan Fang on NS model rat with renal dysfunction and podocyte injury, something which has not been carried out yet. The rats were divided into Normal, Model, Jin Gui Shen Qi Pill (4.12 g/kg), Qi-Dan Fang (3.09, 6.17 and 12.34 g/kg/d) groups, they were each given a single tail intravenous injection of Adriamycin (6.0 mg/kg) except for the Normal group and were orally administered dosages of Qi-Dian Fang and Jin Gui Shen Qi pills once daily for 7 weeks. Following the treatment, the content of cystation C (CysC), blood urea nitrogen (BUN), serum creatinine (Scr) were measured with an autobiochemical analyser. The pathomorphological changes to the glomeruli, the mRNA expressions of nephrin, podocin, CD2AP genes and p53, bax, bcl-2 proteins expressions were also carried out to probe the effects of Qi-Dan Fang. (1) Qi-Dan Fang treatment raised the level of CysC in blood serum while lowering the content of BUN and Scr in the adriamycin-induced nephrotic syndrome rat model; (2) Long-term administration of Qi-Dan Fang was able to ameliorate pathomorphological change of glomeruli and repair the organization structure of Glomerulus; (3) Qi-Dan Fang could increase the mRNA expression of nephrin, podocin and CD2AP genes, down-regulate the

Pirfenidone ameliorates murine chronic GVHD through inhibition of macrophage infiltration and TGF-β production.

PubMed

Du, Jing; Paz, Katelyn; Flynn, Ryan; Vulic, Ante; Robinson, Tara M; Lineburg, Katie E; Alexander, Kylie A; Meng, Jingjing; Roy, Sabita; Panoskaltsis-Mortari, Angela; Loschi, Michael; Hill, Geoffrey R; Serody, Jonathan S; Maillard, Ivan; Miklos, David; Koreth, John; Cutler, Corey S; Antin, Joseph H; Ritz, Jerome; MacDonald, Kelli P; Schacker, Timothy W; Luznik, Leo; Blazar, Bruce R

2017-05-04

Allogeneic hematopoietic stem cell transplantation is hampered by chronic graft-versus-host disease (cGVHD), resulting in multiorgan fibrosis and diminished function. Fibrosis in lung and skin leads to progressive bronchiolitis obliterans (BO) and scleroderma, respectively, for which new treatments are needed. We evaluated pirfenidone, a Food and Drug Administration (FDA)-approved drug for idiopathic pulmonary fibrosis, for its therapeutic effect in cGVHD mouse models with distinct pathophysiology. In a full major histocompatibility complex (MHC)-mismatched, multiorgan system model with BO, donor T-cell responses that support pathogenic antibody production are required for cGVHD development. Pirfenidone treatment beginning one month post-transplant restored pulmonary function and reversed lung fibrosis, which was associated with reduced macrophage infiltration and transforming growth factor-β production. Pirfenidone dampened splenic germinal center B-cell and T-follicular helper cell frequencies that collaborate to produce antibody. In both a minor histocompatibility antigen-mismatched as well as a MHC-haploidentical model of sclerodermatous cGVHD, pirfenidone significantly reduced macrophages in the skin, although clinical improvement of scleroderma was only seen in one model. In vitro chemotaxis assays demonstrated that pirfenidone impaired macrophage migration to monocyte chemoattractant protein-1 (MCP-1) as well as IL-17A, which has been linked to cGVHD generation. Taken together, our data suggest that pirfenidone is a potential therapeutic agent to ameliorate fibrosis in cGVHD. © 2017 by The American Society of Hematology.

Slit2 ameliorates renal inflammation and fibrosis after hypoxia-and lipopolysaccharide-induced epithelial cells injury in vitro

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

Zhou, Xiangjun; Yao, Qisheng, E-mail: yymcyqs@126.com; Sun, Xinbo

Hypoxic acute kidney injury (AKI) is often incompletely repaired and leads to chronic kidney disease (CKD), which is characterized by tubulointerstitial inflammation and fibrosis. The Slit2 family of secreted glycoproteins is expressed in the kidney, it has been shown to exert an anti-inflammatory activity and prevent ischemic renal injury in vivo. However, whether Slit2 reduces renal fibrosis and inflammation after hypoxic and inflammatory epithelial cells injury in vitro remains unknown. In this study, we aimed to evaluate whether Slit2 ameliorated fibrosis and inflammation in two renal epithelial cells line challenged with hypoxia and lipopolysaccharide (LPS). Renal epithelial cells were treatedmore » with hypoxia and LPS to induce cell injury. Hoechst staining and Western blot analysis was conducted to examine epithelial cells injury. Immunofluorescence staining and Western blot analysis was performed to evaluate tubulointerstitial fibrosis. Real-time polymerase chain reaction (PCR) tested the inflammatory factor interleukin (IL)−1β and tumor necrosis factor (TNF)-α, and Western blot analysis determined the hypoxia-inducible factor (HIF)−1α, Toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB. Results revealed that hypoxia induced epithelial cells apoptosis, inflammatory factor IL-1β and TNF-α release and tubulointerstitial fibrosis. LPS could exacerbate hypoxia -induced epithelial cells apoptosis, IL-1β and TNF-α release and fibrosis. Slit2 reduced the expression of fibronectin, the rate of epithelial cell apoptosis, and the expression of inflammatory factor. Slit2 could also inhibit the expression of TLR4 and NF-κB, but not the expression of HIF-1α. Therefore, Slit2 attenuated inflammation and fibrosis after LPS- and hypoxia-induced epithelial cells injury via the TLR4/NF-κB signaling pathway, but not depending on the HIF-1α signaling pathway. - Highlights: • Slit2 ameliorates inflammation after hypoxia-and LPS-induced epithelial cells

Budesonide ameliorates lung injury induced by large volume ventilation.

PubMed

Ju, Ying-Nan; Yu, Kai-Jiang; Wang, Guo-Nian

2016-06-04

Ventilation-induced lung injury (VILI) is a health problem for patients with acute respiratory dysfunction syndrome. The aim of this study was to investigate the effectiveness of budesonide in treating VILI. Twenty-four rats were randomized to three groups: a ventilation group, ventilation/budesonide group, and sham group were ventilated with 30 ml/kg tidal volume or only anesthesia for 4 hor saline or budesonide airway instillation immediately after ventilation. The PaO2/FiO2and wet-to-dry weight ratios, protein concentration, neutrophil count, and neutrophil elastase levels in bronchoalveolar lavage fluid (BALF) and the levels of inflammation-related factors were examined. Histological evaluation of and apoptosis measurement inthe lung were conducted. Compared with that in the ventilation group, the PaO2/FiO2 ratio was significantly increased by treatment with budesonide. The lung wet-to-dry weight ratio, total protein, neutrophil elastase level, and neutrophilcount in BALF were decreased in the budesonide group. The BALF and plasma tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, intercellular adhesion molecule (ICAM)-1, and macrophage inflammatory protein (MIP)-2 levels were decreased, whereas the IL-10 level was increased in the budesonide group. The phosphorylated nuclear factor (NF)-kBlevels in lung tissue were inhibited by budesonide. The histological changes in the lung and apoptosis were reduced by budesonide treatment. Bax, caspase-3, and cleaved caspase-3 were down-regulated, and Bcl-2 was up-regulated by budesonide. Budesonide ameliorated lung injury induced by large volume ventilation, likely by improving epithelial permeability, decreasing edema, inhibiting local and systemic inflammation, and reducing apoptosis in VILI.

Polyunsaturated fatty acids ameliorate aging via redox-telomere-antioncogene axis.

PubMed

Chen, Jingnan; Wei, Yan; Chen, Xinyu; Jiao, Jingjing; Zhang, Yu

2017-01-31

Polyunsaturated fatty acids (PUFA), a group of nourishing and health-promoting nutrients, ameliorate age-related chronic diseases. However, how PUFA especially n-3 PUFA exert anti-aging functions remains poorly understood. Here we link fish oil, docosahexaenoic acid (DHA) and arachidonic acid (AA) to the aging etiology via a redox-telomere-antioncogene axis based on D-galactose-induced aging mice. Both fish oil and PUFA enhanced hepatic superoxide dismutase (SOD) and catalase activities and cardiac SOD activities within the range of 18%-46%, 26%-65% and 19%-58%, respectively, whereas reduced cerebral monoamine oxidase activity, plasma F2-isoprostane level and cerebral lipid peroxidation level by 56%-90%, 20%-79% and 16%-54%, respectively. Thus, PUFA improve the in vivo redox and oxidative stress induced aging process, which however does not exhibit a dose-dependent manner. Notably, both PUFA and fish oil effectively inactivated testicular telomerase and inhibited c-Myc-mediated telomerase reverse transcriptase expression, whereas n-3 PUFA rather than n-6 PUFA protected liver and testes against telomere shortening within the range of 13%-25% and 25%-27%, respectively. Therefore, n-3 PUFA may be better at inhibiting the DNA damage induced aging process. Surprisingly, only DHA significantly suppressed cellular senescence pathway evidenced by testicular antioncogene p16 and p53 expression. This work provides evident support for the crosstalk between PUFA especially n-3 PUFA and the aging process via maintaining the in vivo redox homeostasis, rescuing age-related telomere attrition and down-regulating the antioncogene expression.

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

The immunomodulator AS101 suppresses production of inflammatory cytokines and ameliorates the pathogenesis of experimental autoimmune encephalomyelitis.

PubMed

Xie, Li; Chen, Jing; McMickle, Anthony; Awar, Nadia; Nady, Soad; Sredni, Benjamin; Drew, Paul D; Yu, Shiguang

2014-08-15

We reported that AS101 (organotellurium compound, trichloro(dioxoethylene-O,O') tellurate) inhibited the differentiation of Th17 cells and reduced the production of IL-17 and GM-CSF. In addition, AS101 promoted the production of IL-2 in activated T cells. Flow cytometric analysis showed that AS101 inhibited Th17 cell proliferation. AS101 blocked the activation of transcriptional factor NFAT, Stat3, and RORγt, and increased activation of Erk1/2, suggesting a mechanism of action of AS101. We further demonstrated that AS101 was effective in amelioration of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Finally, by real-time PCR analysis we showed that AS101 reduces the IL-17, IFN-γ, GM-CSF, and IL-6 mRNA expression in inflammatory cells of spinal cords. Additionally, flow cytometry analysis also indicated that the CD4+ T cells and IL-17 and GM-CSF-producing cells were reduced in the spinal cords of AS101 treated mice compared to those treated with PBS. Copyright © 2014 Elsevier B.V. All rights reserved.

The immunomodulator AS101suppresses production of inflammatory cytokines and ameliorates the pathogenesis of experimental autoimmune encephalomyelitis

PubMed Central

Xie, Li; Chen, Jing; McMickle, Anthony; Awar, Nadia; Nady, Soad; Sredni, Benjamin; Drew, Paul D.; Yu, Shiguang

2014-01-01

We reported that AS101 (organotellurium compound, trichloro(dioxoethylene-O,O′) tellurate) inhibited the differentiation of Th17 cells and reduced the production of IL-17 and GM-CSF. In addition, AS101 promoted the production of IL-2 in activated T cells. Flow cytometric analysis showed that AS101 inhibited Th17 cell proliferation. AS101 blocked the activation of transcriptional factor NFAT, Stat3, and RORγt, and increased activation of Erk1/2, suggesting a mechanism of action of AS101. We further demonstrated that AS101 was effective in amelioration of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Finally, by real-time PCR analysis we showed that AS101 reduces the IL-17, IFN-γ, GM-CSF, and IL-6 mRNA expression in inflammatory cells of spinal cords. Additionally, flow cytometry analysis also indicated that the CD4+ T cells and IL-17 and GM-CSF-producing cells were reduced in the spinal cords of AS101 treated mice compared to those treated with PBS. PMID:24975323

Bone marrow mesenchymal stem cells protect against n-hexane-induced neuropathy through beclin 1-independent inhibition of autophagy.

PubMed

Hao, Jie; Li, Shuangyue; Shi, Xiaoxia; Qian, Zhiqiang; Sun, Yijie; Wang, Dunjia; Zhou, Xueying; Qu, Hongxin; Hu, Shuhai; Zuo, Enjun; Zhang, Cong; Hou, Liyan; Wang, Qingshan; Piao, Fengyuan

2018-03-14

Chronic exposure to n-hexane, a widely used organic solvent in industry, induces central-peripheral neuropathy, which is mediated by its active metabolite, 2,5-hexanedione (HD). We recently reported that transplantation of bone marrow-mesenchymal stem cells (BMSC) significantly ameliorated HD-induced neuronal damage and motor deficits in rats. However, the mechanisms remain unclear. Here, we reported that inhibition of HD-induced autophagy contributed to BMSC-afforded protection. BMSC transplantation significantly reduced the levels of microtubule-associated protein 1 light chain 3-II (LC3-II) and the degradation of sequestosome-1 (p62) in the spinal cord and sciatic nerve of HD-intoxicated rats. Downregulation of autophagy by BMSC was also confirmed in VSC4.1 cells exposed to HD. Moreover, inhibition of autophagy by PIK III mitigated the neurotoxic effects of HD and, meanwhile, abolished BMSC-afforded neuroprotection. Furthermore, we found that BMSC failed to interfere with Beclin 1, but promoted activation of mammalian target of rapamycin (mTOR). Unc-like kinse 1 (ULK1) was further recognized as the downstream target of mTOR responsible for BMSC-mediated inhibition of autophagy. Altogether, BMSC transplantation potently ameliorated HD-induced autophagy through beclin 1-independent activation of mTOR pathway, providing a novel insight for the therapeutic effects of BMSC against n-hexane and other environmental toxicants-induced neurotoxicity.

Inhibition of myostatin does not ameliorate disease features of severe spinal muscular atrophy mice.

PubMed

Sumner, Charlotte J; Wee, Claribel D; Warsing, Leigh C; Choe, Dong W; Ng, Andrew S; Lutz, Cathleen; Wagner, Kathryn R

2009-09-01

There is currently no treatment for the inherited motor neuron disease, spinal muscular atrophy (SMA). Severe SMA causes lower motor neuron loss, impaired myofiber development, profound muscle weakness and early mortality. Myostatin is a transforming growth factor-beta family member that inhibits muscle growth. Loss or blockade of myostatin signaling increases muscle mass and improves muscle strength in mouse models of primary muscle disease and in the motor neuron disease, amyotrophic lateral sclerosis. In this study, we evaluated the effects of blocking myostatin signaling in severe SMA mice (hSMN2/delta7SMN/mSmn(-/-)) by two independent strategies: (i) transgenic overexpression of the myostatin inhibitor follistatin and (ii) post-natal administration of a soluble activin receptor IIB (ActRIIB-Fc). SMA mice overexpressing follistatin showed little increase in muscle mass and no improvement in motor function or survival. SMA mice treated with ActRIIB-Fc showed minimal improvement in motor function, and no extension of survival compared with vehicle-treated mice. Together these results suggest that inhibition of myostatin may not be a promising therapeutic strategy in severe forms of SMA.

Baicalin Ameliorates H2O2 Induced Cytotoxicity in HK-2 Cells through the Inhibition of ER Stress and the Activation of Nrf2 Signaling

PubMed Central

Lin, Miao; Li, Long; Zhang, Yi; Zheng, Long; Xu, Ming; Rong, Ruiming; Zhu, Tongyu

2014-01-01

Renal ischemia-reperfusion injury plays a key role in renal transplantation and greatly affects the outcome of allograft. Our previous study proved that Baicalin, a flavonoid glycoside isolated from Scutellaria baicalensis, protects kidney from ischemia-reperfusion injury. This study aimed to study the underlying mechanism in vitro. Human renal proximal tubular epithelial cell line HK-2 cells were stimulated by H2O2 with and without Baicalin pretreatment. The cell viability, apoptosis and oxidative stress level were measured. The expression of endoplasmic reticulum (ER) stress hallmarks, such as binding immunoglobulin protein (BiP) and C/EBP homologous protein (CHOP), were analyzed by western blot and real-time PCR. NF-E2-related factor 2 (Nrf2) expression was also measured. In the H2O2 group, cell viability decreased and cell apoptosis increased. Reactive Oxygen Species (ROS) and Glutathione/Oxidized Glutathione (GSH/GSSG) analysis revealed increased oxidative stress. ER stress and Nrf2 signaling also increased. Baicalin pretreatment ameliorated H2O2-induced cytotoxicity, reduced oxidative stress and ER stress and further activated the anti-oxidative Nrf2 signaling pathway. The inducer of ER stress and the inhibitor of Nrf2 abrogated the protective effects, while the inhibitor of ER stress and the inducer of Nrf2 did not improve the outcome. This study revealed that Baicalin pretreatment serves a protective role against H2O2-induced cytotoxicity in HK-2 cells, where the inhibition of ER stress and the activation of downstream Nrf2 signaling are involved. PMID:25029541

Hydrogen sulfide ameliorated L-NAME-induced hypertensive heart disease by the Akt/eNOS/NO pathway.

PubMed

Jin, Sheng; Teng, Xu; Xiao, Lin; Xue, Hongmei; Guo, Qi; Duan, Xiaocui; Chen, Yuhong; Wu, Yuming

2017-12-01

Reductions in hydrogen sulfide (H 2 S) production have been implicated in the pathogenesis of hypertension; however, no studies have examined the functional role of hydrogen sulfide in hypertensive heart disease. We hypothesized that the endogenous production of hydrogen sulfide would be reduced and exogenous hydrogen sulfide would ameliorate cardiac dysfunction in N ω -nitro- L-arginine methyl ester ( L-NAME)-induced hypertensive rats. Therefore, this study investigated the cardioprotective effects of hydrogen sulfide on L-NAME-induced hypertensive heart disease and explored potential mechanisms. The rats were randomly divided into five groups: Control, Control + sodium hydrosulfide (NaHS), L-NAME, L-NAME + NaHS, and L-NAME + NaHS + glibenclamide (Gli) groups. Systolic blood pressure was monitored each week. In Langendorff-isolated rat heart, cardiac function represented by ±LV dP/dt max and left ventricular developing pressure was recorded after five weeks of treatment. Hematoxylin and Eosin and Masson's trichrome staining and myocardium ultrastructure under transmission electron microscopy were used to evaluate cardiac remodeling. The plasma nitric oxide and hydrogen sulfide concentrations, as well as nitric oxide synthases and cystathionine-γ-lyase activity in left ventricle tissue were determined. The protein expression of p-Akt, Akt, p-eNOS, and eNOS in left ventricle tissue was analyzed using Western blot. After five weeks of L-NAME treatment, there was a time-dependent hypertension, cardiac remodeling, and dysfunction accompanied by a decrease in eNOS phosphorylation, nitric oxide synthase activity, and nitric oxide concentration. Meanwhile, cystathionine-γ-lyase activity and hydrogen sulfide concentration were also decreased. NaHS treatment significantly increased plasma hydrogen sulfide concentration and subsequently promoted the Akt/eNOS/NO pathway which inhibited the development of hypertension and attenuated cardiac remodeling and

Neonatal hippocampal Tat injections: developmental effects on prepulse inhibition (PPI) of the auditory startle response

PubMed Central

Fitting, Sylvia; Booze, Rosemarie M.; Mactutus, Charles F.

2013-01-01

The current estimate of children (<15 years) living with HIV and AIDS is 2.2 million [UNAIDS/WHO, 2005. AIDS Epidemic Update. UNAIDS, Geneva]. The major source of infection occurs through vertical transmission of the virus from mother to child during delivery [UNAIDS/ WHO, 2005. AIDS Epidemic Update. UNAIDS, Geneva]. Recent studies have shown that timing of HIV-1 infection might be related to the onset and rate of progression of CNS disease [Blanche, S., Mayaux, M.-J., Rouziox, C., Teglas, J.-P., Firtion, G., Monpoux, F., Cicaru-Vigneron, N., Meier, F., Tricoire, J., Courpotin, C., Vilmer, E., Griscelli, C., Delfraissy, J.-F., 1994. Relation of the course of HIV infection in children to the severity of the disease in their mothers at delivery. N. Engl. J. Med. 330 (5), 308–312]. The effects of HIV on the brain are thought to be mediated indirectly through the viral toxins Tat and gp120. This study characterized developmental effects on PPI following intrahippocampal administration of Tat. On postnatal day (P)1, one male and one female pup from each of eight Sprague–Dawley litters were bilaterally injected with 50 µg Tat or saline (1 µl volume). Animals were tested for PPI of the auditory startle response (ASR) (ISIs of 0, 8,40, 80, 120, and 4000 ms, six trial blocks, Latin-square design) on days 30, 60 and 90. Tat altered PPI and the pattern of alterations was different for males and females. For males, a leftward shift was evident in the ISI for maximal inhibition of the response on day 30 and on day 60 (χ2(1) = 4.7,p ≤ .03, and χ2(1) = 5.3, p ≤ .02, respectively), but not on day 90. For females, Tat altered peak ASR latency across PPI trials (8–120 ms) at all days of testing (30, 60, and 90 days of age), as indexed by orthogonal component analyses, indicating less modulation of PPI by ISI. Data collected from a second group that were tested only once at 90 days of age, suggested that the observed adverse Tat effects for males and females early in

Biflorin Ameliorates Memory Impairments Induced by Cholinergic Blockade in Mice

PubMed Central

Jeon, Se Jin; Kim, Boseong; Ryu, Byeol; Kim, Eunji; Lee, Sunhee; Jang, Dae Sik; Ryu, Jong Hoon

2017-01-01

To examine the effect of biflorin, a component of Syzygium aromaticum, on memory deficit, we introduced a scopolamine-induced cognitive deficit mouse model. A single administration of biflorin increased latency time in the passive avoidance task, ameliorated alternation behavior in the Y-maze, and increased exploration time in the Morris water maze task, indicating the improvement of cognitive behaviors against cholinergic dysfunction. The biflorin-induced reverse of latency in the scopolamine-treated group was attenuated by MK-801, an NMDA receptor antagonist. Biflorin also enhanced cognitive function in a naïve mouse model. To understand the mechanism of biflorin for memory amelioration, we performed Western blot. Biflorin increased the activation of protein kinase C-ζ and its downstream signaling molecules in the hippocampus. These results suggest that biflorin ameliorates drug-induced memory impairment by modulation of protein kinase C-ζ signaling in mice, implying that biflorin could function as a possible therapeutic agent for the treatment of cognitive problems. PMID:27829270

Amplitude-modulation detection by gerbils in reverberant sound fields.

PubMed

Lingner, Andrea; Kugler, Kathrin; Grothe, Benedikt; Wiegrebe, Lutz

2013-08-01

Reverberation can dramatically reduce the depth of amplitude modulations which are critical for speech intelligibility. Psychophysical experiments indicate that humans' sensitivity to amplitude modulation in reverberation is better than predicted from the acoustic modulation depth at the receiver position. Electrophysiological studies on reverberation in rabbits highlight the contribution of neurons sensitive to interaural correlation. Here, we use a prepulse-inhibition paradigm to quantify the gerbils' amplitude modulation threshold in both anechoic and reverberant virtual environments. Data show that prepulse inhibition provides a reliable method for determining the gerbils' AM sensitivity. However, we find no evidence for perceptual restoration of amplitude modulation in reverberation. Instead, the deterioration of AM sensitivity in reverberant conditions can be quantitatively explained by the reduced modulation depth at the receiver position. We suggest that the lack of perceptual restoration is related to physical properties of the gerbil's ear input signals and inner-ear processing as opposed to shortcomings of their binaural neural processing. Copyright © 2013 Elsevier B.V. All rights reserved.

Berberine ameliorates collagen-induced arthritis in rats by suppressing Th17 cell responses via inducing cortistatin in the gut.

PubMed

Yue, Mengfan; Xia, Yufeng; Shi, Can; Guan, Chunge; Li, Yunfan; Liu, Rui; Wei, Zhifeng; Dai, Yue

2017-09-01

Berberine, an isoquinoline alkaloid, has been reported to ameliorate various autoimmune diseases including rheumatoid arthritis by oral administration. However, its mechanism remains mysterious due to an extremely low bioavailability. The fact that berberine readily accumulates in the gut, the largest endocrine organ in the body, attracted us to explore its anti-arthritic mechanism in view of the induction of intestinal immunosuppressive neuropeptides. In this study, berberine (200 mg·kg -1 , i.g.) was shown to ameliorate collagen-induced arthritis in rats, which was manifested by the reduction of clinical signs and joint destruction, as well as marked down-regulation of Th17 cell frequency and interleukin-17 level in blood. In contrast, an intravenous injection of berberine failed to affect arthritis in rats, implying that its anti-arthritic effect was gut-dependent. Further studies revealed that oral berberine selectively elevated the levels of cortistatin, of five gut-derived neuropeptides tested, in the intestines and sera of arthrititic rats. Antagonists of ghrelin/growth hormone secretagogue receptor 1 (a subtype of cortistatin receptor) almost completely abolished the ameliorative effect of berberine on arthritis and Th17 cell responses in rats. In vitro, berberine showed a moderate ability to promote the expression of cortistatin in nerve cells, which was strengthened when the nerve cells were cocultured with enteroendocrine cells to induce an autocrine/paracrine environment. In summary, oral berberine exerted anti-arthritic effect through inhibiting the Th17 cell response, which was closely associated with the induction of cortistatin generation from gut through augmenting autocrine/paracrine action between enteric nerve cells and endocrine cells. © 2017 Federation of European Biochemical Societies.

The H+/K+ ATPase Inhibitor SCH-28080 Inhibits Insulin Secretion and Induces Cell Death in INS-1E Rat Insulinoma Cells.

PubMed

Jakab, Martin; Ketterl, Nina; Fürst, Johannes; Beyreis, Marlena; Kittl, Michael; Kiesslich, Tobias; Hauser-Kronberger, Cornelia; Gaisberger, Martin; Ritter, Markus

2017-01-01

Glucose-stimulated insulin secretion (GSIS) of pancreatic β-cells involves glucose uptake and metabolism, closure of KATP channels and depolarization of the cell membrane potential (Vmem), activation of voltage-activated Ca2+ currents (ICav) and influx of Ca2+, which eventually triggers hormone exocytosis. Beside this classical pathway, KATP-independent mechanisms such as changes in intracellular pH (pHi) or cell volume, which also affect β-cell viability, can elicit or modify insulin release. In β-cells the regulation of pHi is mainly accomplished by Na+/H+ exchangers (NHEs). To investigate if other proton extrusion mechanisms than NHEs are involved in pH regulation, we tested for the presence of the non-gastric H+/K+ ATPase in rat insulinoma cells and assessed effects of the H+/K+ ATPase inhibitor SCH-28080 on insulin secretion, cell viability and apoptosis. In INS-1E cell cultures, H+/K+ ATPase gene and protein expression was analyzed by reverse transcription PCR and Western blotting. Intracellular pH (pHi) recovery after acute acidic load was measured by NH4Cl prepulsing using BCECF. Insulin secretion was determined by ELISA from the cell culture supernatant. Vmem, K+ and Ca2+ currents were recorded using patch clamp. Overall cell responses were determined using resazurin (viability) and cytotoxicity assays. The mean cell volume (MCV), cell granularity (side-scatter; SSC), phosphatidylserine (PS) exposure, cell membrane integrity, caspase activity and the mitochondrial membrane potential (ΔΨm) were measured by flow cytometry. We found that the α-subunit of the non-gastric H+/K+ ATPase (HKα2) is expressed on mRNA and protein level. However, compared to rat colon tissue, in INS-1E cells mRNA abundance was very low. In NH4Cl prepulsing experiments no K+-dependent pHi recovery was observed under Na+-free extracellular conditions. Nonetheless within 1 h, 20 µM SCH-28080 inhibited GSIS by ∼50%, while basal release was unaffected. The L-type ICav blocker

Ursolic Acid Inhibits Superoxide Production in Activated Neutrophils and Attenuates Trauma-Hemorrhage Shock-Induced Organ Injury in Rats

PubMed Central

Hwang, Tsong-Long; Shen, Hsin-I; Liu, Fu-Chao; Tsai, Hsin-I; Wu, Yang-Chang; Chang, Fang-Rong; Yu, Huang-Ping

2014-01-01

Neutrophil activation is associated with the development of organ injury after trauma–hemorrhagic shock. In the present study, ursolic acid inhibited the superoxide anion generation and elastase release in human neutrophils. Administration of ursolic acid attenuated trauma–hemorrhagic shock-induced hepatic and lung injuries in rats. In addition, administration of ursolic acid attenuated the hepatic malondialdehyde levels and reduced the plasma aspartate aminotransferase and alanine aminotransferase levels after trauma–hemorrhagic shock. In conclusion, ursolic acid, a bioactive natural compound, inhibits superoxide anion generation and elastase release in human neutrophils and ameliorates trauma–hemorrhagic shock-induced organ injury in rats. PMID:25360589

Inhibition of myostatin does not ameliorate disease features of severe spinal muscular atrophy mice

PubMed Central

Sumner, Charlotte J.; Wee, Claribel D.; Warsing, Leigh C.; Choe, Dong W.; Ng, Andrew S.; Lutz, Cathleen; Wagner, Kathryn R.

2009-01-01

There is currently no treatment for the inherited motor neuron disease, spinal muscular atrophy (SMA). Severe SMA causes lower motor neuron loss, impaired myofiber development, profound muscle weakness and early mortality. Myostatin is a transforming growth factor-β family member that inhibits muscle growth. Loss or blockade of myostatin signaling increases muscle mass and improves muscle strength in mouse models of primary muscle disease and in the motor neuron disease, amyotrophic lateral sclerosis. In this study, we evaluated the effects of blocking myostatin signaling in severe SMA mice (hSMN2/delta7SMN/mSmn−/−) by two independent strategies: (i) transgenic overexpression of the myostatin inhibitor follistatin and (ii) post-natal administration of a soluble activin receptor IIB (ActRIIB-Fc). SMA mice overexpressing follistatin showed little increase in muscle mass and no improvement in motor function or survival. SMA mice treated with ActRIIB-Fc showed minimal improvement in motor function, and no extension of survival compared with vehicle-treated mice. Together these results suggest that inhibition of myostatin may not be a promising therapeutic strategy in severe forms of SMA. PMID:19477958

Genipin ameliorates diet-induced obesity via promoting lipid mobilization and browning of white adipose tissue in rats.

PubMed

Guan, Lili; Gong, Dezheng; Yang, Sirao; Shen, Nana; Zhang, Sai; Li, Yuchen; Wu, Qiong; Yuan, Bo; Sun, Yiping; Dai, Ning; Zhu, Liang; Zou, Yuan

2018-04-01

Genipin is the major active component of Gardeniae fructus and has been shown to ameliorate diabetes and insulin resistance in rat models. In this study, we first investigated the effect of genipin on obesity and the related lipid metabolism mechanisms in diet-induced obese rats. Our results showed that genipin reduced body weight, food intake, and visceral fat mass; ameliorated dyslipidemia, glucose intolerance, insulin intolerance, adipocyte hypertrophy, and hepatic steatosis; and reduced serum tumor necrosis factor-α level in diet-induced obese rats. Quantitative real-time reverse-transcription polymerase chain reaction results further illustrated that genipin promoted lipolysis and β-oxidation of fatty acid by upregulating gene expressions of hormone-sensitive lipase and adipose triglyceride lipase in white adipose tissue (WAT) and peroxisome proliferator-activated receptor-α and carnitine palmitoyltransferase 1α in hepatic tissue. Moreover, genipin promoted browning of WAT by upregulating the mRNA and protein levels of uncoupling protein 1 and PRD1-BF1-RIZ1 homologous domain containing 16 in WAT. Additionally, genipin inhibited gene expressions of activin receptor-like kinase 7, tumor necrosis factor-α, and interlukin-6 in WAT. These results indicated that genipin had a potential therapeutic role in obesity, in which regulation of lipid mobilization and browning of WAT were involved. Copyright © 2018 John Wiley & Sons, Ltd.

Molecular Mechanism of Betaine on Hepatic Lipid Metabolism: Inhibition of Forkhead Box O1 (FoxO1) Binding to Peroxisome Proliferator-Activated Receptor Gamma (PPARγ).

PubMed

Kim, Dae Hyun; Lee, Bonggi; Kim, Min Jo; Park, Min Hi; An, Hye Jin; Lee, Eun Kyeong; Chung, Ki Wung; Park, June Whoun; Yu, Byung Pal; Choi, Jae Sue; Chung, Hae Young

2016-09-14

Betaine is a major water-soluble component of Lycium chinensis. Although there are reports about the protective effects of betaine on hepatic steatosis, the underlying mechanisms are unclear. We used db/db mice and HepG2 cells to examine the mechanism underlying betaine-mediated protection against hepatic steatosis. Here, we showed increased hepatic lipid accumulation in db/db mice, which is associated with increased activation of lipogenic transcription factors including forkhead box O1 (FoxO1) and peroxisome proliferator-activated receptor gamma (PPARγ), whereas betaine administration by oral gavage reversed these characteristics. We investigated whether betaine ameliorates hepatic steatosis by inhibiting FoxO1/PPARγ signaling in HepG2 cells. Although adenovirus-mediated FoxO1 overexpression notably increased mRNA expression levels of PPARγ and its target genes including FAS and ACC, betaine treatment reversed them. Furthermore, betaine inhibited FoxO1 binding to the PPARγ promoter and PPARγ transcriptional activity in HepG2 cells, which was previously shown to induce hepatic steatosis. We concluded that betaine ameliorates hepatic steatosis, at least in part, by inhibiting the FoxO1 binding to PPARγ and their downstream lipogenic signaling cascade.

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

PubMed Central

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

2016-01-01

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

Propofol inhibits NF-κB activation to ameliorate airway inflammation in ovalbumin (OVA)-induced allergic asthma mice.

PubMed

Zhang, Qiong; Wang, Liangrong; Chen, Baihui; Zhuo, Qian; Bao, Caiying; Lin, Lina

2017-10-01

Propofol, one of the most commonly used intravenous anesthetic agents, has been reported to have anti-inflammatory property. However, the anti-allergic inflammation effect of propofol and its underlying molecular mechanisms have not been elucidated. In the present study, we aim to investigate the roles of NF-kB activation in propofol anti-asthma effect on OVA-induced allergic airway inflammation in mice. In a standard experimental asthma model, Balb/c mice were sensitized with ovalbumin, treated with propofol (50,100,150mg/kg) or a vehicle control 1h before OVA challenge. Blood samples, bronchoalveolar lavage fluid (BALF) and lung tissues were harvested after measurement of airway hyperresponsiveness. Results revealed that propofol not only significantly inhibit airway hyperresponsiveness, but also inhibited the production of Th2 cytokines, NO, Ova-specific IgE and eotaxin. Histological studies indicated that propofol significantly attenuated OVA-induced inflammatory cell infiltration in the peribronchial areas and mucus hypersecretion. Meanwhile, our results indicated that propofol was found to inhibit NF-kB activation in OVA-Induced mice. Furthermore, propofol significantly reduced the TNF-α-induced NF-kB activation in A549 cells. In conclusion, our study suggested that propofol effectively reduced allergic airway inflammation by inhibiting NF-kB activation and could thus be used as a therapy for allergic asthma. Copyright © 2017. Published by Elsevier B.V.

Inhibition of Na+/H+ exchanger enhances low pH-induced L-selectin shedding and β2-integrin surface expression in human neutrophils

PubMed Central

Kaba, Nubia K.; Schultz, Joanne; Law, Foon-Yee; Lefort, Craig T.; Martel-Gallegos, Guadalupe; Kim, Minsoo; Waugh, Richard E.; Arreola, Jorge; Knauf, Philip A.

2008-01-01

Ischemia-reperfusion injury is a common pathological occurrence causing tissue damage in heart attack and stroke. Entrapment of neutrophils in the vasculature during ischemic events has been implicated in this process. In this study, we examine the effects that lactacidosis and consequent reductions in intracellular pH (pHi) have on surface expression of adhesion molecules on neutrophils. When human neutrophils were exposed to pH 6 lactate, there was a marked decrease in surface L-selectin (CD62L) levels, and the decrease was significantly enhanced by inclusion of Na+/H+ exchanger (NHE) inhibitor 5-(N,N-hexamethylene)amiloride (HMA). Similar effects were observed when pHi was reduced while maintaining normal extracellular pH, by using an NH4Cl prepulse followed by washes and incubation in pH 7.4 buffer containing NHE inhibitors [HMA, cariporide, or 5-(N,N-dimethyl)amiloride (DMA)]. The amount of L-selectin shedding induced by different concentrations of NH4Cl in the prepulse correlated with the level of intracellular acidification with an apparent pK of 6.3. In contrast, β2-integrin (CD11b and CD18) was only slightly upregulated in the low-pHi condition and was enhanced by NHE inhibition to a much lesser extent. L-selectin shedding was prevented by treating human neutrophils with inhibitors of extracellular metalloproteases (RO-31-9790 and KD-IX-73-4) or with inhibitors of intracellular signaling via p38 MAP kinase (SB-203580 and SB-239063), implying a transmembrane effect of pHi. Taken together, these data suggest that the ability of NHE inhibitors such as HMA to reduce ischemia-reperfusion injury may be related to the nearly complete removal of L-selectin from the neutrophil surface. PMID:18829897

Thiopental Inhibits Global Protein Synthesis by Repression of Eukaryotic Elongation Factor 2 and Protects from Hypoxic Neuronal Cell Death

PubMed Central

Schwer, Christian I.; Lehane, Cornelius; Guelzow, Timo; Zenker, Simone; Strosing, Karl M.; Spassov, Sashko; Erxleben, Anika; Heimrich, Bernd; Buerkle, Hartmut; Humar, Matjaz

2013-01-01

Ischemic and traumatic brain injury is associated with increased risk for death and disability. The inhibition of penumbral tissue damage has been recognized as a target for therapeutic intervention, because cellular injury evolves progressively upon ATP-depletion and loss of ion homeostasis. In patients, thiopental is used to treat refractory intracranial hypertension by reducing intracranial pressure and cerebral metabolic demands; however, therapeutic benefits of thiopental-treatment are controversially discussed. In the present study we identified fundamental neuroprotective molecular mechanisms mediated by thiopental. Here we show that thiopental inhibits global protein synthesis, which preserves the intracellular energy metabolite content in oxygen-deprived human neuronal SK-N-SH cells or primary mouse cortical neurons and thus ameliorates hypoxic cell damage. Sensitivity to hypoxic damage was restored by pharmacologic repression of eukaryotic elongation factor 2 kinase. Translational inhibition was mediated by calcium influx, activation of the AMP-activated protein kinase, and inhibitory phosphorylation of eukaryotic elongation factor 2. Our results explain the reduction of cerebral metabolic demands during thiopental treatment. Cycloheximide also protected neurons from hypoxic cell death, indicating that translational inhibitors may generally reduce secondary brain injury. In conclusion our study demonstrates that therapeutic inhibition of global protein synthesis protects neurons from hypoxic damage by preserving energy balance in oxygen-deprived cells. Molecular evidence for thiopental-mediated neuroprotection favours a positive clinical evaluation of barbiturate treatment. The chemical structure of thiopental could represent a pharmacologically relevant scaffold for the development of new organ-protective compounds to ameliorate tissue damage when oxygen availability is limited. PMID:24167567

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

PubMed

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

2013-04-01

Fibroblast growth factor 23 (FGF23) is a circulating factor secreted by osteocytes that is essential for phosphate homeostasis. In kidney proximal tubular cells FGF23 inhibits phosphate reabsorption and leads to decreased synthesis and enhanced catabolism of 1,25-dihydroxyvitamin D3 (1,25[OH]2 D3 ). Excess levels of FGF23 cause renal phosphate wasting and suppression of circulating 1,25(OH)2 D3 levels and are associated with several hereditary hypophosphatemic disorders with skeletal abnormalities, including X-linked hypophosphatemic rickets (XLH) and autosomal recessive hypophosphatemic rickets (ARHR). Currently, therapeutic approaches to these diseases are limited to treatment with activated vitamin D analogues and phosphate supplementation, often merely resulting in partial correction of the skeletal aberrations. In this study, we evaluate the use of FGFR inhibitors for the treatment of FGF23-mediated hypophosphatemic disorders using NVP-BGJ398, a novel selective, pan-specific FGFR inhibitor currently in Phase I clinical trials for cancer therapy. In two different hypophosphatemic mouse models, Hyp and Dmp1-null mice, resembling the human diseases XLH and ARHR, we find that pharmacological inhibition of FGFRs efficiently abrogates aberrant FGF23 signaling and normalizes the hypophosphatemic and hypocalcemic conditions of these mice. Correspondingly, long-term FGFR inhibition in Hyp mice leads to enhanced bone growth, increased mineralization, and reorganization of the disturbed growth plate structure. We therefore propose NVP-BGJ398 treatment as a novel approach for the therapy of FGF23-mediated hypophosphatemic diseases. Copyright © 2013 American Society for Bone and Mineral Research.

RNA interference against stromal interacting molecule-1 (STIM1) ameliorates ethanol-induced hepatotoxicity.

PubMed

Cui, Ruibing; Li, Rong; Guo, Xiaolan; Jia, Xiaoqing; Yan, Ming

2018-06-01

Previously we have demonstrated that stromal interacting molecule-1 (STIM1) was involved in ethanol induced liver injury. However, the exact pathogenic mechanism of STIM1 in alcoholic liver disease (ALD) is still unknown. We constructed plasmid vectors encoding short-hairpin RNA against STIM1 to investigate its role in ALD in the rat liver cell line BRL and in Sprague-Dawley rats. The results showed that STIM1 targeted sh-RNA (Sh-STIM1) significantly ameliorated ethanol-induced BRL cells injury and liver injury in rats with 20 weeks-induced alcoholic liver disease. Inhibition of STIM1 also reduced intracellular calcium ion concentration, reactive oxygen species (ROS) production, lipid peroxidation, NF-kappa B activation and TNF-α production under ethanol exposure. STIM1 may play an important role in the pathogenesis of alcoholic liver disease. Silencing STIM1 may be effective in preventing alcoholic liver disease. Copyright © 2018 Elsevier B.V. All rights reserved.

Oxaloacetate Ameliorates Chemical Liver Injury via Oxidative Stress Reduction and Enhancement of Bioenergetic Fluxes.

PubMed

Kuang, Ye; Han, Xiaoyun; Xu, Mu; Wang, Yue; Zhao, Yuxiang; Yang, Qing

2018-05-31

Chemical injury is partly due to free radical lipid peroxidation, which can induce oxidative stress and produce a large number of reactive oxygen species (ROS). Oxaloacetic acid is an important intermediary in the tricarboxylic acid cycle (TCA cycle) and participates in metabolism and energy production. In our study, we found that oxaloacetate (OA) effectively alleviated liver injury which was induced by hydrogen peroxide (H₂O₂) in vitro and carbon tetrachloride (CCl₄) in vivo. OA scavenged ROS, prevented oxidative damage and maintained the normal structure of mitochondria. We further confirmed that OA increased adenosine triphosphate (ATP) by promoting the TCA production cycle and oxidative phosphorylation (OXPHOS). Finally, OA inhibited the mitogen-activated protein kinase (MAPK) and apoptotic pathways by suppressing tumor necrosis factor-α (TNF-α). Our findings reveal a mechanism for OA ameliorating chemical liver injury and suggest a possible implementation for preventing the chemical liver injury.

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

PubMed Central

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

2014-01-01

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

Calpastatin inhibits motor neuron death and increases survival of hSOD1(G93A) mice.

PubMed

Rao, Mala V; Campbell, Jabbar; Palaniappan, Arti; Kumar, Asok; Nixon, Ralph A

2016-04-01

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with a poorly understood cause and no effective treatment. Given that calpains mediate neurodegeneration in other pathological states and are abnormally activated in ALS, we investigated the possible ameliorative effects of inhibiting calpain over-activation in hSOD1(G93A) transgenic (Tg) mice in vivo by neuron-specific over-expression of calpastatin (CAST), the highly selective endogenous inhibitor of calpains. Our data indicate that over-expression of CAST in hSOD1(G93A) mice, which lowered calpain activation to levels comparable to wild-type mice, inhibited the abnormal breakdown of cytoskeletal proteins (spectrin, MAP2 and neurofilaments), and ameliorated motor axon loss. Disease onset in hSOD1(G93A) /CAST mice compared to littermate hSOD1(G93A) mice is delayed, which accounts for their longer time of survival. We also find that neuronal over-expression of CAST in hSOD1(G93A) transgenic mice inhibited production of putative neurotoxic caspase-cleaved tau and activation of Cdk5, which have been implicated in neurodegeneration in ALS models, and also reduced the formation of SOD1 oligomers. Our data indicate that inhibition of calpain with CAST is neuroprotective in an ALS mouse model. CAST (encoding calpastatin) inhibits hyperactivated calpain to prevent motor neuron disease operating through a cascade of events as indicated in the schematic, with relevance to amyotrophic lateral sclerosis (ALS). We propose that over-expression of CAST in motor neurons of hSOD1(G93A) mice inhibits activation of CDK5, breakdown of cytoskeletal proteins (NFs, MAP2 and Tau) and regulatory molecules (Cam Kinase IV, Calcineurin A), and disease-causing proteins (TDP-43, α-Synuclein and Huntingtin) to prevent neuronal loss and delay neurological deficits. In our experiments, CAST could also inhibit cleavage of Bid, Bax, AIF to prevent mitochondrial, ER and lysosome-mediated cell death mechanisms. Similarly, CAST

Rapamycin ameliorates IgA nephropathy via cell cycle-dependent mechanisms

PubMed Central

Tian, Jihua; Wang, Yanhong; Liu, Xinyan; Zhou, Xiaoshuang

2014-01-01

IgA nephropathy is the most frequent type of glomerulonephritis worldwide. The role of cell cycle regulation in the pathogenesis of IgA nephropathy has been studied. The present study was designed to explore whether rapamycin ameliorates IgA nephropathy via cell cycle-dependent mechanisms. After establishing an IgA nephropathy model, rats were randomly divided into four groups. Coomassie Brilliant Blue was used to measure the 24-h urinary protein levels. Renal function was determined using an autoanalyzer. Proliferation was assayed via Proliferating Cell Nuclear Antigen (PCNA) immunohistochemistry. Rat mesangial cells were cultured and divided into the six groups. Methylthiazolyldiphenyl-tetrazolium bromide (MTT) and flow cytometry were used to detect cell proliferation and the cell cycle phase. Western blotting was performed to determine cyclin E, cyclin-dependent kinase 2, p27Kip1, p70S6K/p-p70S6K, and extracellular signal-regulated kinase 1/2/p- extracellular signal-regulated kinase 1/2 protein expression. A low dose of the mammalian target of rapamycin (mTOR) inhibitor rapamycin prevented an additional increase in proteinuria, protected kidney function, and reduced IgA deposition in a model of IgA nephropathy. Rapamycin inhibited mesangial cell proliferation and arrested the cell cycle in the G1 phase. Rapamycin did not affect the expression of cyclin E and cyclin-dependent kinase 2. However, rapamycin upregulated p27Kip1 at least in part via AKT (also known as protein kinase B)/mTOR. In conclusion, rapamycin can affect cell cycle regulation to inhibit mesangial cell proliferation, thereby reduce IgA deposition, and slow the progression of IgAN. PMID:25349217

Ameliorating effect of Yokukansan on the development of atopic dermatitis-like lesions and scratching behavior in socially isolated NC/Nga mice.

PubMed

Funakushi, Naoko; Yamaguchi, Takuji; Jiang, Ju; Imamura, Sachiko; Kuhara, Takatoshi; Suto, Hajime; Ueki, Rie; Kase, Yoshio; Kobayashi, Hiroyuki; Ogawa, Hideoki; Ikeda, Shigaku

2011-11-01

Yokukansan (YKS) has been used in Japan as a remedy for neurosis, insomnia, and children with night crying. In a previous study, we reported that YKS controls scratching behavior and inhibits the development of atopic dermatitis (AD)-like lesions in NC/Nga mice. In this study, we investigated the effects of YKS on the development of AD-like lesions in socially isolated NC/Nga mice compared with the effects of fexofenadine and elucidated the mechanism of the ameliorating effect of YKS on the skin lesions. Ten-week-old male NC/Nga mice were divided into three groups (n = 5/group): the conventional control, the YKS-treated, and the fexofenadine-treated groups, and were kept isolated under conventional conditions for 6 weeks. Measurements were made of dermatitis scores and transepidermal water loss (TEWL), scratching and grooming behaviors. Immunohistochemistry and mRNA levels were also evaluated. We performed similar experiments under specific pathogen free (SPF) conditions that served as a SPF control. YKS and fexofenadine inhibited the aggravation of skin lesions and decreased TEWL, but only YKS decreased the numbers of scratching and pathologic grooming behaviors. Immunohistochemistry and RT-PCR revealed that N-methyl-D: -aspartate (NMDA) receptor expression was increased in the skin of conventional control mice and was decreased in YKS-treated mice. Glutamate transporter-1 (GLT-1) mRNA levels were decreased in the skin of conventional control mice and were increased in YKS-treated mice. The results indicate that YKS ameliorates AD-like skin lesions in NC/Nga mice through a mechanism distinct from that of fexofenadine. Furthermore, the effects of YKS are suggested to be mediated via glutamate signaling in the skin lesions.

Nitric Oxide Ameliorates Zinc Oxide Nanoparticles Phytotoxicity in Wheat Seedlings: Implication of the Ascorbate–Glutathione Cycle

PubMed Central

Tripathi, Durgesh K.; Mishra, Rohit K.; Singh, Swati; Singh, Samiksha; Vishwakarma, Kanchan; Sharma, Shivesh; Singh, Vijay P.; Singh, Prashant K.; Prasad, Sheo M.; Dubey, Nawal K.; Pandey, Avinash C.; Sahi, Shivendra; Chauhan, Devendra K.

2017-01-01

The present study investigates ameliorative effects of nitric oxide (NO) against zinc oxide nanoparticles (ZnONPs) phytotoxicity in wheat seedlings. ZnONPs exposure hampered growth of wheat seedlings, which coincided with reduced photosynthetic efficiency (Fv/Fm and qP), due to increased accumulation of zinc (Zn) in xylem and phloem saps. However, SNP supplementation partially mitigated the ZnONPs-mediated toxicity through the modulation of photosynthetic activity and Zn accumulation in xylem and phloem saps. Further, the results reveal that ZnONPs treatments enhanced levels of hydrogen peroxide and lipid peroxidation (as malondialdehyde; MDA) due to severely inhibited activities of the following ascorbate–glutatione cycle (AsA–GSH) enzymes: ascorbate peroxidase, glutathione reductase, monodehydroascorbate reductase and dehydroascorbate reductase, and its associated metabolites ascorbate and glutathione. In contrast to this, the addition of SNP together with ZnONPs maintained the cellular functioning of the AsA–GSH cycle properly, hence lesser damage was noticed in comparison to ZnONPs treatments alone. The protective effect of SNP against ZnONPs toxicity on fresh weight (growth) can be reversed by 2-(4carboxy-2-phenyl)-4,4,5,5-tetramethyl- imidazoline-1-oxyl-3-oxide, a NO scavenger, and thus suggesting that NO released from SNP ameliorates ZnONPs toxicity. Overall, the results of the present study have shown the role of NO in the reducing of ZnONPs toxicity through the regulation of accumulation of Zn as well as the functioning of the AsA–GSH cycle. PMID:28220127

A novel phosphodiesterase-5 Inhibitor: Yonkenafil modulates neurogenesis, gliosis to improve cognitive function and ameliorates amyloid burden in an APP/PS1 transgenic mice model.

PubMed

Zhu, Lei; Yang, Jing-yu; Xue, Xue; Dong, Ying-xu; Liu, Yang; Miao, Feng-rong; Wang, Yong-feng; Xue, Hong; Wu, Chun-fu

2015-09-01

In Alzheimer's disease (AD), activated microglia invade and surround β-amyloid plaques, possibly contributing to the aggregation of amyloid β (Aβ), which affect the survival of neurons and lead to memory loss. Phosphodiesterase-5 (PDE-5) inhibitors have recently been shown a potential therapeutic effect on AD. In this study, the effects of yonkenafil (yonk), a novel PDE-5 inhibitor, on cognitive behaviors as well as the pathological features in transgenic AD mice were investigated. Seven-month-old APP/PS1 transgenic mice were treated with yonk (2, 6, or 18 mg/kg, intraperitoneal injection (i.p.)) or sildenafil (sild) (6 mg/kg, i.p.) daily for 3 months and then behavioral tests were performed. The results demonstrated that yonk improved nesting-building ability, ameliorated working memory deficits in the Y-maze tasks, and significantly improved learning and memory function in the Morris water maze (MWM) tasks. In addition, yonk reduced the area of Aβ plaques, and inhibited over-activation of microglia and astrocytes. Furthermore, yonk increased neurogenesis in the dentate granule brain region of APP/PS1 mice, indicated by increased BrdU(+)/NeuN(+) and BrdU(+)/DCX(+) cells compared to vehicle-treated transgenic mice. These results suggest that yonk could rescue cognitive deficits by ameliorated amyloid burden through regulating APP processing, inhibited the over-activation of microglia and astrocytes as well as restored neurogenesis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Lacosamide Inhibition of Nav1.7 Voltage-Gated Sodium Channels: Slow Binding to Fast-Inactivated States

PubMed Central

Jo, Sooyeon

2017-01-01

Lacosamide is an antiseizure agent that targets voltage-dependent sodium channels. Previous experiments have suggested that lacosamide is unusual in binding selectively to the slow-inactivated state of sodium channels, in contrast to drugs like carbamazepine and phenytoin, which bind tightly to fast-inactivated states. Using heterologously expressed human Nav1.7 sodium channels, we examined the state-dependent effects of lacosamide. Lacosamide induced a reversible shift in the voltage dependence of fast inactivation studied with 100-millisecond prepulses, suggesting binding to fast-inactivated states. Using steady holding potentials, lacosamide block was very weak at −120 mV (3% inhibition by 100 µM lacosamide) but greatly enhanced at −80 mV (43% inhibition by 100 µM lacosamide), where there is partial fast inactivation but little or no slow inactivation. During long depolarizations, lacosamide slowly (over seconds) put channels into states that recovered availability slowly (hundreds of milliseconds) at −120 mV. This resembles enhancement of slow inactivation, but the effect was much more pronounced at −40 mV, where fast inactivation is complete, but slow inactivation is not, than at 0 mV, where slow inactivation is maximal, more consistent with slow binding to fast-inactivated states than selective binding to slow-inactivated states. Furthermore, inhibition by lacosamide was greatly reduced by pretreatment with 300 µM lidocaine or 300 µM carbamazepine, suggesting that lacosamide, lidocaine, and carbamazepine all bind to the same site. The results suggest that lacosamide binds to fast-inactivated states in a manner similar to other antiseizure agents but with slower kinetics of binding and unbinding. PMID:28119481

Lacosamide Inhibition of Nav1.7 Voltage-Gated Sodium Channels: Slow Binding to Fast-Inactivated States.

PubMed

Jo, Sooyeon; Bean, Bruce P

2017-04-01

Lacosamide is an antiseizure agent that targets voltage-dependent sodium channels. Previous experiments have suggested that lacosamide is unusual in binding selectively to the slow-inactivated state of sodium channels, in contrast to drugs like carbamazepine and phenytoin, which bind tightly to fast-inactivated states. Using heterologously expressed human Nav1.7 sodium channels, we examined the state-dependent effects of lacosamide. Lacosamide induced a reversible shift in the voltage dependence of fast inactivation studied with 100-millisecond prepulses, suggesting binding to fast-inactivated states. Using steady holding potentials, lacosamide block was very weak at -120 mV (3% inhibition by 100 µ M lacosamide) but greatly enhanced at -80 mV (43% inhibition by 100 µ M lacosamide), where there is partial fast inactivation but little or no slow inactivation. During long depolarizations, lacosamide slowly (over seconds) put channels into states that recovered availability slowly (hundreds of milliseconds) at -120 mV. This resembles enhancement of slow inactivation, but the effect was much more pronounced at -40 mV, where fast inactivation is complete, but slow inactivation is not, than at 0 mV, where slow inactivation is maximal, more consistent with slow binding to fast-inactivated states than selective binding to slow-inactivated states. Furthermore, inhibition by lacosamide was greatly reduced by pretreatment with 300 µ M lidocaine or 300 µ M carbamazepine, suggesting that lacosamide, lidocaine, and carbamazepine all bind to the same site. The results suggest that lacosamide binds to fast-inactivated states in a manner similar to other antiseizure agents but with slower kinetics of binding and unbinding. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Pyrolysis temperature influences ameliorating effects of biochars on acidic soil.

PubMed

Wan, Qing; Yuan, Jin-Hua; Xu, Ren-Kou; Li, Xing-Hui

2014-02-01

The biochars were prepared from straws of canola, corn, soybean, and peanut at different temperatures of 300, 500, and 700 °C by means of oxygen-limited pyrolysis.Amelioration effects of these biochars on an acidic Ultisol were investigated with incubation experiments, and application rate of biochars was 10 g/kg. The incorporation of these biochars induced the increase in soil pH, soil exchangeable base cations, base saturation, and cation exchange capacity and the decrease in soil exchangeable acidity and exchangeable Al. The ameliorating effects of biochars on acidic soil increased with increase in their pyrolysis temperature. The contribution of oxygen-containing functional groups on the biochars to their ameliorating effects on the acidic soil decreased with the rise in pyrolysis temperature, while the contribution from carbonates in the biochars changed oppositely. The incorporation of the biochars led to the decrease in soil reactive Al extracted by 0.5mol/L CuCl2, and the content of reactive Al was decreased with the increase in pyrolysis temperature of incorporated biochars. The biochars generated at 300 °C increased soil organically complexed Al due to ample quantity of oxygen-containing functional groups such as carboxylic and phenolic groups on the biochars, while the biochars generated at 500 and 700 °C accelerated the transformation of soil exchangeable Al to hydroxyl-Al polymers due to hydrolysis of Al at higher pH. Therefore, the crop straw-derived biochars can be used as amendments for acidic soils and the biochars generated at relatively high temperature have great ameliorating effects on the soils.

Topical atorvastatin ameliorates 12-O-tetradecanoylphorbol-13-acetate induced skin inflammation by reducing cutaneous cytokine levels and NF-κB activation.

PubMed

Kulkarni, Nagaraj M; Muley, Milind M; Jaji, Mallikarjun S; Vijaykanth, G; Raghul, J; Reddy, Neetin Kumar D; Vishwakarma, Santosh L; Rajesh, Navin B; Mookkan, Jeyamurugan; Krishnan, Uma Maheswari; Narayanan, Shridhar

2015-06-01

Atorvastatin is a 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor used in the treatment of atherosclerosis and dyslipidemia. Studies have evaluated the utility of statins in the treatment of skin inflammation but with varied results. In the present study, we investigated the effect of atorvastatin on TNF-α release and keratinocyte proliferation in vitro and in acute and chronic 12-O-tetradecanoylphorbol-13-acetate (TPA) induced skin inflammation in vivo. Atorvastatin significantly inhibited lipopolysacharide induced TNF-α release in THP-1 cells and keratinocyte proliferation in HaCaT cells. In an acute study, topical atorvastatin showed dose dependent reduction in TPA induced skin inflammation with highest efficacy observed at 500 µg/ear dose. In chronic study, topical atorvastatin significantly reduced TPA induced ear thickness, ear weight, cutaneous cytokines, MPO activity and improved histopathological features comparable to that of dexamethasone. Atorvastatin also inhibited TPA stimulated NF-κB activation in mouse ear. In conclusion, our results suggest that atorvastatin ameliorates TPA induced skin inflammation in mice at least in part, due to inhibition of cytokine release and NF-κB activation and may be beneficial for the treatment skin inflammation like psoriasis.

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.

PubMed

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. Copyright © 2014 Elsevier Inc. All rights reserved.

SIRT2 ameliorates lipopolysaccharide-induced inflammation in macrophages

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

Lee, Ae Sin; Jung, Yu Jin; Kim, Dal

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 macrophagesmore » 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

Patchouli alcohol ameliorates dextran sodium sulfate-induced experimental colitis and suppresses tryptophan catabolism.

PubMed

Qu, Chang; Yuan, Zhong-Wen; Yu, Xiu-Ting; Huang, Yan-Feng; Yang, Guang-Hua; Chen, Jian-Nan; Lai, Xiao-Ping; Su, Zi-Ren; Zeng, Hui-Fang; Xie, Ying; Zhang, Xiao-Jun

2017-07-01

Despite the increased morbidity of ulcerative colitis (UC) in recent years, available treatments remain unsatisfactory. Pogostemon cablin has been widely applied to treat a variety of gastrointestinal disorders in clinic for centuries, in which patchouli alcohol (PA, C 15 H 26 O) has been identified as the major active component. This study attempted to determine the bioactivity of PA on dextran sulfate sodium (DSS)-induced mice colitis and clarify the mechanism of action. Acute colitis was induced in mice by 3% DSS for 7 days. The mice were then given PA (10, 20 and 40mg/kg) or sulfasalazine (SASP, 200mg/kg) as positive control via oral administration for 7 days. At the end of study, animals were sacrificed and samples were collected for pathological and other analysis. In addition, a metabolite profiling and a targeted metabolite analysis, based on the Ultra-Performance Liquid Chromatography coupled with mass spectrometry (UPLC-MS) approach, were performed to characterize the metabolic changes in plasma. The results revealed that PA significantly reduced the disease activity index (DAI) and ameliorated the colonic injury of DSS mice. The levels of colonic MPO and cytokines involving TNF-α, IFN-γ, IL-1β, IL-6, IL-4 and IL-10 also declined. Furthermore, PA improved the intestinal epithelial barrier by enhancing the level of colonic expression of the tight junction (TJ) proteins, for instance ZO-1, ZO-2, claudin-1 and occludin, and by elevating the levels of mucin-1 and mucin-2 mRNA. The study also demonstrated that PA inhibited the DSS-induced cell death signaling by modulating the apoptosis related Bax and Bcl-2 proteins and down-regulating the necroptosis related RIP3 and MLKL proteins. By comparison, up-regulation of IDO-1 and TPH-1 protein expression in DSS group was suppressed by PA, which was in line with the declined levels of kynurenine (Kyn) and 5-hydroxytryptophan (5-HTP) in plasma. The therapeutic effect of PA was evidently reduced when Kyn was given

The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells

PubMed Central

2011-01-01

Introduction The aim was to determine the effect of the Bruton tyrosine kinase (Btk)-selective inhibitor PCI-32765, currently in Phase I/II studies in lymphoma trials, in arthritis and immune-complex (IC) based animal models and describe the underlying cellular mechanisms. Methods PCI-32765 was administered in a series of murine IC disease models including collagen-induced arthritis (CIA), collagen antibody-induced arthritis (CAIA), reversed passive anaphylactic reaction (RPA), and passive cutaneous anaphylaxis (PCA). Clinical and pathologic features characteristic of each model were examined following treatment. PCI-32765 was then examined in assays using immune cells relevant to the pathogenesis of arthritis, and where Btk is thought to play a functional role. These included proliferation and calcium mobilization in B cells, cytokine and chemokine production in monocytes/macrophages, degranulation of mast cells and its subsequent cytokine/chemokine production. Results PCI-32765 dose-dependently and potently reversed arthritic inflammation in a therapeutic CIA model with an ED50 of 2.6 mg/kg/day. PCI-32765 also prevented clinical arthritis in CAIA models. In both models, infiltration of monocytes and macrophages into the synovium was completely inhibited and importantly, the bone and cartilage integrity of the joints were preserved. PCI-32765 reduced inflammation in the Arthus and PCA assays. In vitro, PCI-32765 inhibited BCR-activated primary B cell proliferation (IC50 = 8 nM). Following FcγR stimulation, PCI-32765 inhibited TNFα, IL-1β and IL-6 production in primary monocytes (IC50 = 2.6, 0.5, 3.9 nM, respectively). Following FcεRI stimulation of cultured human mast cells, PCI-32765 inhibited release of histamine, PGD2, TNF-α, IL-8 and MCP-1. Conclusions PCI-32765 is efficacious in CIA, and in IC models that do not depend upon autoantibody production from B cells. Thus PCI-32765 targets not only B lymphocytes but also monocytes, macrophages and mast cells

Caffeine protects against experimental acute pancreatitis by inhibition of inositol 1,4,5-trisphosphate receptor-mediated Ca2+ release

PubMed Central

Huang, Wei; Cane, Matthew C; Mukherjee, Rajarshi; Szatmary, Peter; Zhang, Xiaoying; Elliott, Victoria; Ouyang, Yulin; Chvanov, Michael; Latawiec, Diane; Wen, Li; Booth, David M; Haynes, Andrea C; Petersen, Ole H; Tepikin, Alexei V; Criddle, David N

2017-01-01

Objective Caffeine reduces toxic Ca2+ signals in pancreatic acinar cells via inhibition of inositol 1,4,5-trisphosphate receptor (IP3R)-mediated signalling, but effects of other xanthines have not been evaluated, nor effects of xanthines on experimental acute pancreatitis (AP). We have determined effects of caffeine and its xanthine metabolites on pancreatic acinar IP3R-mediated Ca2+ signalling and experimental AP. Design Isolated pancreatic acinar cells were exposed to secretagogues, uncaged IP3 or toxins that induce AP and effects of xanthines, non-xanthine phosphodiesterase (PDE) inhibitors and cyclic adenosine monophosphate and cyclic guanosine monophosphate (cAMP/cGMP) determined. The intracellular cytosolic calcium concentration ([Ca2+]C), mitochondrial depolarisation and necrosis were assessed by confocal microscopy. Effects of xanthines were evaluated in caerulein-induced AP (CER-AP), taurolithocholic acid 3-sulfate-induced AP (TLCS-AP) or palmitoleic acid plus ethanol-induced AP (fatty acid ethyl ester AP (FAEE-AP)). Serum xanthines were measured by liquid chromatography-mass spectrometry. Results Caffeine, dimethylxanthines and non-xanthine PDE inhibitors blocked IP3-mediated Ca2+ oscillations, while monomethylxanthines had little effect. Caffeine and dimethylxanthines inhibited uncaged IP3-induced Ca2+ rises, toxin-induced Ca2+ release, mitochondrial depolarisation and necrotic cell death pathway activation; cAMP/cGMP did not inhibit toxin-induced Ca2+ rises. Caffeine significantly ameliorated CER-AP with most effect at 25 mg/kg (seven injections hourly); paraxanthine or theophylline did not. Caffeine at 25 mg/kg significantly ameliorated TLCS-AP and FAEE-AP. Mean total serum levels of dimethylxanthines and trimethylxanthines peaked at >2 mM with 25 mg/kg caffeine but at <100 µM with 25 mg/kg paraxanthine or theophylline. Conclusions Caffeine and its dimethylxanthine metabolites reduced pathological IP3R-mediated pancreatic acinar Ca2

Critical role of renal dipeptidyl peptidase-4 in ameliorating kidney injury induced by saxagliptin in Dahl salt-sensitive hypertensive rats.

PubMed

Sakai, Mariko; Uchii, Masako; Myojo, Kensuke; Kitayama, Tetsuya; Kunori, Shunji

2015-08-15

Saxagliptin, a potent dipeptidyl peptidase-4 (DPP-4) inhibitor, is currently used to treat type 2 diabetes mellitus, and it has been reported to exhibit a slower rate of dissociation from DPP-4 compared with another DPP-4 inhibitor, sitagliptin. In this study, we compared the effects of saxagliptin and sitagliptin on hypertension-related renal injury and the plasma and renal DPP-4 activity levels in Dahl salt-sensitive hypertensive (Dahl-S) rats. The high-salt diet (8% NaCl) significantly increased the blood pressure and quantity of urinary albumin excretion and induced renal glomerular injury in the Dahl-S rats. Treatment with saxagliptin (14mg/kg/day via drinking water) for 4 weeks significantly suppressed the increase in urinary albumin excretion and tended to ameliorate glomerular injury without altering the blood glucose levels and systolic blood pressure. On the other hand, the administration of sitagliptin (140mg/kg/day via drinking water) did not affect urinary albumin excretion and glomerular injury in the Dahl-S rats. Meanwhile, the high-salt diet increased the renal DPP-4 activity but did not affect the plasma DPP-4 activity in the Dahl-S rats. Both saxagliptin and sitagliptin suppressed the plasma DPP-4 activity by 95% or more. Although the renal DPP-4 activity was also inhibited by both drugs, the inhibitory effect of saxagliptin was more potent than that of sitagliptin. These results indicate that saxagliptin has a potent renoprotective effect in the Dahl-S rats, independent of its glucose-lowering actions. The inhibition of the renal DPP-4 activity induced by saxagliptin may contribute to ameliorating renal injury in hypertension-related renal injury. Copyright © 2015 Elsevier B.V. All rights reserved.

Bilateral Renal Denervation Ameliorates Isoproterenol-Induced Heart Failure through Downregulation of the Brain Renin-Angiotensin System and Inflammation in Rat

PubMed Central

Li, Jian-Dong; Cheng, Ai-Yuan; Huo, Yan-Li; Fan, Jie; Zhang, Yu-Ping; Fang, Zhi-Qin; Sun, Hong-Sheng; Peng, Wei; Zhang, Jin-Shun

2016-01-01

Heart failure (HF) is characterized by cardiac dysfunction along with autonomic unbalance that is associated with increased renin-angiotensin system (RAS) activity and elevated levels of proinflammatory cytokines (PICs). Renal denervation (RD) has been shown to improve cardiac function in HF, but the protective mechanisms remain unclear. The present study tested the hypothesis that RD ameliorates isoproterenol- (ISO-) induced HF through regulation of brain RAS and PICs. Chronic ISO infusion resulted in remarked decrease in blood pressure (BP) and increase in heart rate and cardiac dysfunction, which was accompanied by increased BP variability and decreased baroreflex sensitivity and HR variability. Most of these adverse effects of ISO on cardiac and autonomic function were reversed by RD. Furthermore, ISO upregulated mRNA and protein expressions of several components of the RAS and PICs in the lamina terminalis and hypothalamic paraventricular nucleus, two forebrain nuclei involved in cardiovascular regulations. RD significantly inhibited the upregulation of these genes. Either intracerebroventricular AT1-R antagonist, irbesartan, or TNF-α inhibitor, etanercept, mimicked the beneficial actions of RD in the ISO-induced HF. The results suggest that the RD restores autonomic balance and ameliorates ISO-induced HF and that the downregulated RAS and PICs in the brain contribute to these beneficial effects of RD. PMID:27746855

The Amelioration of Olfactory Acuity upon Sexual Maturation Might Affect Food Preferences

PubMed Central

Bignetti, Enrico; Sinesio, Fiorella; Aiello, Gaetano L.; Cannella, Carlo

2009-01-01

Upon sexual maturation, olfactory acuity in women ameliorates and starts oscillating across the cycle. During ovulation, mean olfactory threshold is 30 times lower than during bleeding. Interestingly, menstruated women undergo maleodorant trimethylaminuria. We argued that olfactory amelioration during ovulation might concur to a mating strategy, whereas olfactory impairment during bleeding might protect women against self-refusal. Testosterone and its 17β-estradiol derivative might be responsible for the synchronization of these menstrual events. Furthermore, we posed the question whether olfactory detection amelioration upon sexual maturation might provoke a change in food preferences, for instance a reduction in fish consumption. A preliminary survey in Italy provided encouraging results: 15-44 year-old women have lower fish consumption than 3-14 year-old girls. Surprisingly, men exhibited the same behaviour, so new olfactory tests as well as testosterone measurements are under way. PMID:22253964

Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation

PubMed Central

Steinbicker, Andrea U.; Sachidanandan, Chetana; Vonner, Ashley J.; Yusuf, Rushdia Z.; Deng, Donna Y.; Lai, Carol S.; Rauwerdink, Kristen M.; Winn, Julia C.; Saez, Borja; Cook, Colleen M.; Szekely, Brian A.; Roy, Cindy N.; Seehra, Jasbir S.; Cuny, Gregory D.; Scadden, David T.; Peterson, Randall T.; Bloch, Kenneth D.

2011-01-01

Anemia of inflammation develops in settings of chronic inflammatory, infectious, or neoplastic disease. In this highly prevalent form of anemia, inflammatory cytokines, including IL-6, stimulate hepatic expression of hepcidin, which negatively regulates iron bioavailability by inactivating ferroportin. Hepcidin is transcriptionally regulated by IL-6 and bone morphogenetic protein (BMP) signaling. We hypothesized that inhibiting BMP signaling can reduce hepcidin expression and ameliorate hypoferremia and anemia associated with inflammation. In human hepatoma cells, IL-6–induced hepcidin expression, an effect that was inhibited by treatment with a BMP type I receptor inhibitor, LDN-193189, or BMP ligand antagonists noggin and ALK3-Fc. In zebrafish, the induction of hepcidin expression by transgenic expression of IL-6 was also reduced by LDN-193189. In mice, treatment with IL-6 or turpentine increased hepcidin expression and reduced serum iron, effects that were inhibited by LDN-193189 or ALK3-Fc. Chronic turpentine treatment led to microcytic anemia, which was prevented by concurrent administration of LDN-193189 or attenuated when LDN-193189 was administered after anemia was established. Our studies support the concept that BMP and IL-6 act together to regulate iron homeostasis and suggest that inhibition of BMP signaling may be an effective strategy for the treatment of anemia of inflammation. PMID:21393479

PPARγ antagonist attenuates mouse immune-mediated bone marrow failure by inhibition of T cell function

PubMed Central

Sato, Kazuya; Feng, Xingmin; Chen, Jichun; Li, Jungang; Muranski, Pawel; Desierto, Marie J.; Keyvanfar, Keyvan; Malide, Daniela; Kajigaya, Sachiko; Young, Neal S.

2016-01-01

Acquired aplastic anemia is an immune-mediated disease, in which T cells target hematopoietic cells; at presentation, the bone marrow is replaced by fat. It was reported that bone marrow adipocytes were negative regulators of hematopoietic microenvironment. To examine the role of adipocytes in bone marrow failure, we investigated peroxisomal proliferator-activated receptor gamma, a key transcription factor in adipogenesis, utilizing an antagonist of this factor called bisphenol-A-diglycidyl-ether. While bisphenol-A-diglycidyl-ether inhibited adipogenesis as expected, it also suppressed T cell infiltration of bone marrow, reduced plasma inflammatory cytokines, decreased expression of multiple inflammasome genes, and ameliorated marrow failure. In vitro, bisphenol-A-diglycidyl-ether suppressed activation and proliferation, and reduced phospholipase C gamma 1 and nuclear factor of activated T-cells 1 expression, as well as inhibiting calcium flux in T cells. The in vivo effect of bisphenol-A-diglycidyl-ether on T cells was confirmed in a second immune-mediated bone marrow failure model, using different strains and non-major histocompatibility antigen mismatched: bisphenol-A-diglycidyl-ether ameliorated marrow failure by inhibition of T cell infiltration of bone marrow. Our data indicate that peroxisomal proliferator-activated receptor gamma antagonists may attenuate murine immune-mediated bone marrow failure, at least in part, by suppression of T cell activation, which might hold implications in the application of peroxisomal proliferator-activated receptor gamma antagonists in immune-mediated pathophysiologies, both in the laboratory and in the clinic. Genetically “fatless” mice developed bone marrow failure with accumulation of marrow adipocytes in our model, even in the absence of body fat, suggesting different mechanisms of systematic and marrow adipogenesis and physiologic versus pathophysiologic fat accumulation. PMID:26589913

Grape seed procyanidin B2 ameliorates mitochondrial dysfunction and inhibits apoptosis via the AMP-activated protein kinase-silent mating type information regulation 2 homologue 1-PPARγ co-activator-1α axis in rat mesangial cells under high-dose glucosamine.

PubMed

Bao, Lei; Cai, Xiaxia; Zhang, Zhaofeng; Li, Yong

2015-01-14

Grape seed procyanidin B2 (GSPB2), an antioxidative and anti-inflammatory polyphenol in grape seed, has been found to have protective effects on diabetic nephropathy. Based on its favourable biological activities, in the present study, we aimed to investigate whether GSPB2 could inhibit apoptosis in rat mesangial cells treated with glucosamine (GlcN) under high-dose conditions. The results showed that the administration of GSPB2 (10 μg/ml) significantly increased the viability of mesangial cells treated with GlcN at a dose of 15 mM. We found that GSPB2 inhibited apoptosis in mesangial cells using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphates (dUTP) nick-end labelling staining and flow cytometry technique (P< 0·05 for both). GSPB2 treatment also suppressed oxidative stress by elevating the activity of glutathione peroxidase (P< 0·05) and superoxide dismutase (P< 0·01), as well as prevented cellular damage. GSPB2 enhanced the mRNA expression of nuclear respiratory factor 1, mitochondrial transcription factor A and mitochondrial DNA copy number in mesangial cells as determined by real-time PCR (P< 0·05 for each). Finally, GSPB2 treatment activated the protein expression of PPARγ co-activator-1α (PGC-1α), silent mating type information regulation 2 homologue 1 (SIRT1) and AMP-activated protein kinase (AMPK) in mesangial cells. These findings suggest that GSPB2 markedly ameliorates mitochondrial dysfunction and inhibits apoptosis in rat mesangial cells treated with high-dose GlcN. This protective effect could be, at least in part, due to the activation of the AMPK-SIRT1-PGC-1α axis.

Ginsenoside Ameliorates Cognitive Dysfunction in Type 2 Diabetic Goto-Kakizaki Rats.

PubMed

Tian, Zhiyan; Ren, Ning; Wang, Jinghua; Zhang, Danhong; Zhou, Yuying

2018-06-10

BACKGROUND Ginsenoside is the major bioactive component of ginseng, which has been proven to be a neuroprotective drug. The aim of this study was to evaluate the therapeutic effect of ginsenoside in a diabetic Goto-Kakizaki (GK) rat model. MATERIAL AND METHODS Twenty GK rats were randomly divided into a diabetic model (DM) group (n=10) and a ginsenoside + DM group (n=10); Wistar rats with the same age and body weight were used as the control (CON) group (n=10). Food and water intake, body weight, and blood fasting plasma glucose were measured. The Morris water maze test was used to detect learning and memory functions of the rats. Superoxide dismutase (SOD), malondialdehyde (MDA), and inflammatory cytokines (TNF-α, IL-1β, and IL-6) in the hippocampus were analyzed after ginsenoside treatment. RESULTS The blood glucose, body weight, Morris correlation index, SOD, MDA, and other test results were increased in the diabetic rats. Ginsenoside ameliorated diabetic cognitive decline. CONCLUSIONS The possible mechanism was related to inhibiting brain oxidative/nitrosative damage and affecting the expression of the cytokines IL-1β, IL-6, and TNF-α.

Regulation of Th1 and Th17 cell differentiation and amelioration of experimental autoimmune encephalomyelitis by natural product compound berberine.

PubMed

Qin, Xia; Guo, Bingshi T; Wan, Bing; Fang, Lei; Lu, Limin; Wu, Lili; Zang, Ying Qin; Zhang, Jingwu Z

2010-08-01

Berberine (BBR), an isoquinoline alkaloid derived from plants, is widely used as an anti-inflammatory remedy in traditional Chinese medicine. In this study, we showed that BBR was efficacious in the amelioration of experimental autoimmune encephalomyelitis (EAE) through novel regulatory mechanisms involving pathogenic Th1 and Th17 cells. BBR inhibited differentiation of Th17 cells and, to a lesser degree, Th1 cells through direct actions on the JAK/STAT pathway, whereas it had no effect on the relative number of CD4(+)Foxp3(+) regulatory T cells. In addition, BBR indirectly influenced Th17 and Th1 cell functions through its effect on the expression and function of costimulatory molecules and the production of IL-6, which was attributable to the inhibition of NF-kappaB activity in CD11b(+) APCs. BBR treatment completely abolished the encephalitogenicity of MOG(35-55)-reactive Th17 cells in an adoptive transfer EAE model, and the same treatment significantly inhibited the ability of MOG(35-55)-reactive Th1 cells to induce EAE. This study provides new evidence that natural compounds, such as BBR, are of great value in the search for novel anti-inflammatory agents and therapeutic targets for autoimmune diseases.

Estrogen amelioration of Aβ-induced defects in mitochondria is mediated by mitochondrial signaling pathway involving ERβ, AKAP and Drp1.

PubMed

Sarkar, Saumyendra; Jun, Sujung; Simpkins, James W

2015-08-07

Perturbations in dynamic properties of mitochondria including fission, fusion, and movement lead to disruption of energy supply to synapses contributing to neuropathology and cognitive dysfunction in Alzheimer׳s disease (AD). The molecular mechanisms underlying these defects are still unclear. Previously, we have shown that ERβ is localized in the mitochondria and ERβ knock down disrupts mitochondrial functions. Because a selective ERβ modulator (DPN) can activate PKA, and localized PKA signaling in the mitochondrial membrane regulates mitochondrial structure and functions, we reasoned that ERβ signaling in the mitochondrial membrane rescues many of the mitochondrial defects caused by soluble Aβ oligomer. We now report that DPN treatment in primary hippocampal neurons attenuates soluble Aβ-oligomer induced dendritic mitochondrial fission and reduced mobility. Additionally, Aβ treatment reduced the respiratory reserve capacity of hippocampal neuron and inhibited phosphorylation of Drp1 at its PKA site, which induces excessive mitochondrial fission, and DPN treatment ameliorates these inhibitions. Finally, we discovered a direct interaction of ERβ with a mitochondrial resident protein AKAP1, which induces the PKA-mediated local signaling pathway involved in increased oxidative phosphorylation and inhibition of mitochondrial fission. Taken together, our findings highlight the possibility that ERβ signaling pathway may be a useful mitochondria-directed therapeutic target for AD. Copyright © 2015 Elsevier B.V. All rights reserved.

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.

Nicotinamide mononucleotide inhibits post-ischemic NAD(+) degradation and dramatically ameliorates brain damage following global cerebral ischemia.

PubMed

Park, Ji H; Long, Aaron; Owens, Katrina; Kristian, Tibor

2016-11-01

Nicotinamide adenine dinucleotide (NAD(+)) is an essential cofactor for multiple cellular metabolic reactions and has a central role in energy production. Brain ischemia depletes NAD(+) pools leading to bioenergetics failure and cell death. Nicotinamide mononucleotide (NMN) is utilized by the NAD(+) salvage pathway enzyme, nicotinamide adenylyltransferase (Nmnat) to generate NAD(+). Therefore, we examined whether NMN could protect against ischemic brain damage. Mice were subjected to transient forebrain ischemia and treated with NMN or vehicle at the start of reperfusion or 30min after the ischemic insult. At 2, 4, and 24h of recovery, the proteins poly-ADP-ribosylation (PAR), hippocampal NAD(+) levels, and expression levels of NAD(+) salvage pathway enzymes were determined. Furthermore, animal's neurologic outcome and hippocampal CA1 neuronal death was assessed after six days of reperfusion. NMN (62.5mg/kg) dramatically ameliorated the hippocampal CA1 injury and significantly improved the neurological outcome. Additionally, the post-ischemic NMN treatment prevented the increase in PAR formation and NAD(+) catabolism. Since the NMN administration did not affect animal's temperature, blood gases or regional cerebral blood flow during recovery, the protective effect was not a result of altered reperfusion conditions. These data suggest that administration of NMN at a proper dosage has a strong protective effect against ischemic brain injury. Published by Elsevier Inc.

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.

Inhibition of Sphingosine Kinase 1 Ameliorates Angiotensin II-Induced Hypertension and Inhibits Transmembrane Calcium Entry via Store-Operated Calcium Channel

PubMed Central

Wilson, Parker C.; Fitzgibbon, Wayne R.; Garrett, Sara M.; Jaffa, Ayad A.; Luttrell, Louis M.; Brands, Michael W.

2015-01-01

Angiotensin II (AngII) plays a critical role in the regulation of vascular tone and blood pressure mainly via regulation of Ca2+ mobilization. Several reports have implicated sphingosine kinase 1 (SK1)/sphingosine 1-phosphate (S1P) in the mobilization of intracellular Ca2+ through a yet-undefined mechanism. Here we demonstrate that AngII-induces biphasic calcium entry in vascular smooth muscle cells, consisting of an immediate peak due to inositol tris-phosphate-dependent release of intracellular calcium, followed by a sustained transmembrane Ca2+ influx through store-operated calcium channels (SOCs). Inhibition of SK1 attenuates the second phase of transmembrane Ca2+ influx, suggesting a role for SK1 in AngII-dependent activation of SOC. Intracellular S1P triggers SOC-dependent Ca2+ influx independent of S1P receptors, whereas external application of S1P stimulated S1P receptor-dependent Ca2+ influx that is insensitive to inhibitors of SOCs, suggesting that the SK1/S1P axis regulates store-operated calcium entry via intracellular rather than extracellular actions. Genetic deletion of SK1 significantly inhibits both the acute hypertensive response to AngII in anaesthetized SK1 knockout mice and the sustained hypertensive response to continuous infusion of AngII in conscious animals. Collectively these data implicate SK1 as the missing link that connects the angiotensin AT1A receptor to transmembrane Ca2+ influx and identify SOCs as a potential intracellular target for SK1. PMID:25871850

Rapamycin ameliorates IgA nephropathy via cell cycle-dependent mechanisms.

PubMed

Tian, Jihua; Wang, Yanhong; Liu, Xinyan; Zhou, Xiaoshuang; Li, Rongshan

2015-07-01

IgA nephropathy is the most frequent type of glomerulonephritis worldwide. The role of cell cycle regulation in the pathogenesis of IgA nephropathy has been studied. The present study was designed to explore whether rapamycin ameliorates IgA nephropathy via cell cycle-dependent mechanisms. After establishing an IgA nephropathy model, rats were randomly divided into four groups. Coomassie Brilliant Blue was used to measure the 24-h urinary protein levels. Renal function was determined using an autoanalyzer. Proliferation was assayed via Proliferating Cell Nuclear Antigen (PCNA) immunohistochemistry. Rat mesangial cells were cultured and divided into the six groups. Methylthiazolyldiphenyl-tetrazolium bromide (MTT) and flow cytometry were used to detect cell proliferation and the cell cycle phase. Western blotting was performed to determine cyclin E, cyclin-dependent kinase 2, p27(Kip1), p70S6K/p-p70S6K, and extracellular signal-regulated kinase 1/2/p- extracellular signal-regulated kinase 1/2 protein expression. A low dose of the mammalian target of rapamycin (mTOR) inhibitor rapamycin prevented an additional increase in proteinuria, protected kidney function, and reduced IgA deposition in a model of IgA nephropathy. Rapamycin inhibited mesangial cell proliferation and arrested the cell cycle in the G1 phase. Rapamycin did not affect the expression of cyclin E and cyclin-dependent kinase 2. However, rapamycin upregulated p27(Kip1) at least in part via AKT (also known as protein kinase B)/mTOR. In conclusion, rapamycin can affect cell cycle regulation to inhibit mesangial cell proliferation, thereby reduce IgA deposition, and slow the progression of IgAN. © 2014 by the Society for Experimental Biology and Medicine.

Esculeogenin A, a new tomato sapogenol, ameliorates hyperlipidemia and atherosclerosis in ApoE-deficient mice by inhibiting ACAT.

PubMed

Fujiwara, Yukio; Kiyota, Naoko; Hori, Masaharu; Matsushita, Sayaka; Iijima, Yoko; Aoki, Koh; Shibata, Daisuke; Takeya, Motohiro; Ikeda, Tsuyoshi; Nohara, Toshihiro; Nagai, Ryoji

2007-11-01

We recently identified esculeoside A, a new spirosolane-type glycoside, with a content in tomatoes that is 4-fold higher than that of lycopene. In the present study, we examined the effects of esculeoside A and esculeogenin A, a new aglycon of esculeoside A, on foam cell formation in vitro and atherogenesis in apoE-deficient mice. Esculeogenin A significantly inhibited the accumulation of cholesterol ester (CE) induced by acetylated low density lipoprotein (acetyl-LDL) in human monocyte-derived macrophages (HMDM) in a dose-dependent manner without inhibiting triglyceride accumulation, however, it did not inhibit the association of acetyl-LDL to the cells. Esculeogenin A also inhibited CE formation in Chinese hamster ovary cells overexpressing acyl-coenzymeA (CoA): cholesterol acyl-transferase (ACAT)-1 or ACAT-2, suggesting that esculeogenin A suppresses the activity of both ACAT-1 and ACAT-2. Furthermore, esculeogenin A prevented the expression of ACAT-1 protein, whereas that of SR-A and SR-BI was not suppressed. Oral administration of esculeoside A to apoE-deficient mice significantly reduced the levels of serum cholesterol, triglycerides, LDL-cholesterol, and the areas of atherosclerotic lesions without any detectable side effects. Our study provides the first evidence that purified esculeogenin A significantly suppresses the activity of ACAT protein and leads to reduction of atherogenesis.

Paeoniflorin ameliorates AGEs-induced mesangial cell injury through inhibiting RAGE/mTOR/autophagy pathway.

PubMed

Chen, Juan; Zhao, Di; Zhu, Maomao; Zhang, Minghua; Hou, Xuefeng; Ding, Wenbo; Sun, Shuai; Bu, Weiquan; Feng, Liang; Ma, Shiping; Jia, Xiaobin

2017-05-01

Glomerular mesangial cell plays a vital role in diabetic nephropathy (DN). Recent research has demonstrated that autophagy involved in the development of DN. Paeoniflorin (PF), a monoterpene glucoside, has been proved to attenuate advanced glycation end products (AGEs)-induced mesangial cell injury. However, the regulatory mechanism of PF on autophagy in mesangial cell remains unclear. The aim of this study was to explore the effect of PF on autophagy in AGEs-induced mesangial cell dysfunction. In this study, the leakage of the lactic dehydrogenase (LDH) into the extracellular medium was measured by LDH kit. Transmission electron microscopy (TEM) and mRFP-GFP-microtubule-associated protein light chain 3 (LC3) transfection were performed to observe the formation of autophagy in AGEs-induced mesangial cell. The RAGE/mTOR/autophagy pathway was analyzed by western blotting and small-interfering RNA transfection. Our results showed that the expression of LC3II, p62 were changed in a time-dependent manner in AGEs-stimulated mesangial cell. While PF could decrease the expression of LC3II/LC3I and reduce the number of autophagosomes. Knockdown of Atg5 promoted the protective effect of PF on AGEs-induced HBZY-1 injury. Furthermore, we found PF inhibited autophagy at least partly through inhibiting RAGE and upregulating the level of p-mTOR to against AGEs-induced mesangial cell dysfunction. Thus, PF could be a potential agent for the treatment of DN. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Brief Report: Sensorimotor Gating in Idiopathic Autism and Autism Associated with Fragile X Syndrome

ERIC Educational Resources Information Center

Yuhas, Jennifer; Cordeiro, Lisa; Tassone, Flora; Ballinger, Elizabeth; Schneider, Andrea; Long, James M.; Ornitz, Edward M.; Hessl, David

2011-01-01

Prepulse inhibition (PPI) may useful for exploring the proposed shared neurobiology between idiopathic autism and autism caused by FXS. We compared PPI in four groups: typically developing controls (n = 18), FXS and autism (FXS+A; n = 15), FXS without autism spectrum disorder (FXS-A; n = 17), and idiopathic autism (IA; n = 15). Relative to…

Aronia melanocarpa Extract Ameliorates Hepatic Lipid Metabolism through PPARγ2 Downregulation

PubMed Central

Kim, Jung-Hee; Lee, Eun Byul; Hur, Wonhee; Kwon, Oh-Joo; Park, Hyoung-Jin; Yoon, Seung Kew

2017-01-01

Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. Studies have demonstrated that anthocyanin-rich foods may improve hyperlipidemia and ameliorate hepatic steatosis. Here, effects of Aronia melanocarpa (AM), known to be rich of anthocyanins, on hepatic lipid metabolism and adipogenic genes were determined. AM was treated to C57BL/6N mice fed with high fat diet (HFD) or to FL83B cells treated with free fatty acid (FFA). Changes in levels of lipids, enzymes and hormones were observed, and expressions of adipogenic genes involved in hepatic lipid metabolism were detected by PCR, Western blotting and luciferase assay. In mice, AM significantly reduced the body and liver weight, lipid accumulation in the liver, and levels of biochemical markers such as fatty acid synthase, hepatic triglyceride and leptin. Serum transaminases, indicators for hepatocyte injury, were also suppressed, while superoxide dismutase activity and liver antioxidant capacity were significantly increased. In FL83B cells, AM significantly reduced FFA-induced lipid droplet accumulation. Protein synthesis of an adipogenic transcription factor, peroxisome proliferator-activated receptor γ2 (PPARγ2) was inhibited in vivo. Furthermore, transcriptional activity of PPARγ2 was down-regulated in vitro, and mRNA expression of PPARγ2 and its downstream target genes, adipocyte protein 2 and lipoprotein lipase were down-regulated by AM both in vitro and in vivo. These results show beneficial effects of AM against hepatic lipid accumulation through the inhibition of PPARγ2 expression along with improvements in body weight, liver functions, lipid profiles and antioxidant capacity suggesting the potential therapeutic efficacy of AM on NAFLD. PMID:28081181

Aronia melanocarpa Extract Ameliorates Hepatic Lipid Metabolism through PPARγ2 Downregulation.

PubMed

Park, Chung-Hwa; Kim, Jung-Hee; Lee, Eun Byul; Hur, Wonhee; Kwon, Oh-Joo; Park, Hyoung-Jin; Yoon, Seung Kew

2017-01-01

Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. Studies have demonstrated that anthocyanin-rich foods may improve hyperlipidemia and ameliorate hepatic steatosis. Here, effects of Aronia melanocarpa (AM), known to be rich of anthocyanins, on hepatic lipid metabolism and adipogenic genes were determined. AM was treated to C57BL/6N mice fed with high fat diet (HFD) or to FL83B cells treated with free fatty acid (FFA). Changes in levels of lipids, enzymes and hormones were observed, and expressions of adipogenic genes involved in hepatic lipid metabolism were detected by PCR, Western blotting and luciferase assay. In mice, AM significantly reduced the body and liver weight, lipid accumulation in the liver, and levels of biochemical markers such as fatty acid synthase, hepatic triglyceride and leptin. Serum transaminases, indicators for hepatocyte injury, were also suppressed, while superoxide dismutase activity and liver antioxidant capacity were significantly increased. In FL83B cells, AM significantly reduced FFA-induced lipid droplet accumulation. Protein synthesis of an adipogenic transcription factor, peroxisome proliferator-activated receptor γ2 (PPARγ2) was inhibited in vivo. Furthermore, transcriptional activity of PPARγ2 was down-regulated in vitro, and mRNA expression of PPARγ2 and its downstream target genes, adipocyte protein 2 and lipoprotein lipase were down-regulated by AM both in vitro and in vivo. These results show beneficial effects of AM against hepatic lipid accumulation through the inhibition of PPARγ2 expression along with improvements in body weight, liver functions, lipid profiles and antioxidant capacity suggesting the potential therapeutic efficacy of AM on NAFLD.

Cannabinoids and Vanilloids in Schizophrenia: Neurophysiological Evidence and Directions for Basic Research

PubMed Central

Ruggiero, Rafael N.; Rossignoli, Matheus T.; De Ross, Jana B.; Hallak, Jaime E. C.; Leite, Joao P.; Bueno-Junior, Lezio S.

2017-01-01

Much of our knowledge of the endocannabinoid system in schizophrenia comes from behavioral measures in rodents, like prepulse inhibition of the acoustic startle and open-field locomotion, which are commonly used along with neurochemical approaches or drug challenge designs. Such methods continue to map fundamental mechanisms of sensorimotor gating, hyperlocomotion, social interaction, and underlying monoaminergic, glutamatergic, and GABAergic disturbances. These strategies will require, however, a greater use of neurophysiological tools to better inform clinical research. In this sense, electrophysiology and viral vector-based circuit dissection, like optogenetics, can further elucidate how exogenous cannabinoids worsen (e.g., tetrahydrocannabinol, THC) or ameliorate (e.g., cannabidiol, CBD) schizophrenia symptoms, like hallucinations, delusions, and cognitive deficits. Also, recent studies point to a complex endocannabinoid-endovanilloid interplay, including the influence of anandamide (endogenous CB1 and TRPV1 agonist) on cognitive variables, such as aversive memory extinction. In fact, growing interest has been devoted to TRPV1 receptors as promising therapeutic targets. Here, these issues are reviewed with an emphasis on the neurophysiological evidence. First, we contextualize imaging and electrographic findings in humans. Then, we present a comprehensive review on rodent electrophysiology. Finally, we discuss how basic research will benefit from further combining psychopharmacological and neurophysiological tools. PMID:28680405

Cannabinoids and Vanilloids in Schizophrenia: Neurophysiological Evidence and Directions for Basic Research.

PubMed

Ruggiero, Rafael N; Rossignoli, Matheus T; De Ross, Jana B; Hallak, Jaime E C; Leite, Joao P; Bueno-Junior, Lezio S

2017-01-01

Much of our knowledge of the endocannabinoid system in schizophrenia comes from behavioral measures in rodents, like prepulse inhibition of the acoustic startle and open-field locomotion, which are commonly used along with neurochemical approaches or drug challenge designs. Such methods continue to map fundamental mechanisms of sensorimotor gating, hyperlocomotion, social interaction, and underlying monoaminergic, glutamatergic, and GABAergic disturbances. These strategies will require, however, a greater use of neurophysiological tools to better inform clinical research. In this sense, electrophysiology and viral vector-based circuit dissection, like optogenetics, can further elucidate how exogenous cannabinoids worsen (e.g., tetrahydrocannabinol, THC) or ameliorate (e.g., cannabidiol, CBD) schizophrenia symptoms, like hallucinations, delusions, and cognitive deficits. Also, recent studies point to a complex endocannabinoid-endovanilloid interplay, including the influence of anandamide (endogenous CB 1 and TRPV 1 agonist) on cognitive variables, such as aversive memory extinction. In fact, growing interest has been devoted to TRPV 1 receptors as promising therapeutic targets. Here, these issues are reviewed with an emphasis on the neurophysiological evidence. First, we contextualize imaging and electrographic findings in humans. Then, we present a comprehensive review on rodent electrophysiology. Finally, we discuss how basic research will benefit from further combining psychopharmacological and neurophysiological tools.

Pharmacologic Treatment with GABAB Receptor Agonist of Methamphetamine-Induced Cognitive Impairment in Mice

PubMed Central

Mizoguchi, Hiroyuki; Yamada, Kiyofumi

2011-01-01

Methamphetamine (METH) is a highly addictive drug, and addiction to METH has increased to epidemic proportions worldwide. Chronic use of METH causes psychiatric symptoms, such as hallucinations and delusions, and long-term cognitive deficits, which are indistinguishable from paranoid schizophrenia. The GABA receptor system is known to play a significant role in modulating the dopaminergic neuronal system, which is related to behavioral changes induced by drug abuse. However, few studies have investigated the effects of GABA receptor agonists on cognitive deficits induced by METH. In the present review, we show that baclofen, a GABA receptor agonist, is effective in treating METH-induced impairment of object recognition memory and prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating in mice. Acute and repeated treatment with METH induced a significant impairment of PPI. Furthermore, repeated but not acute treatment of METH resulted in a long-lasting deficit of object recognition memory. Baclofen, a GABAB receptor agonist, dose-dependently ameliorated the METH-induced PPI deficits and object recognition memory impairment in mice. On the other hand, THIP, a GABAA receptor agonist, had no effect on METH-induced cognitive deficits. These results suggest that GABAB receptors may constitute a putative new target in treating cognitive deficits in chronic METH users. PMID:21886573

Kidney-targeted inhibition of protein kinase C-α ameliorates nephrotoxic nephritis with restoration of mitochondrial dysfunction.

PubMed

Kvirkvelia, Nino; McMenamin, Malgorzata; Warren, Marie; Jadeja, Ravirajsinh N; Kodeboyina, Sai Karthik; Sharma, Ashok; Zhi, Wenbo; O'Connor, Paul M; Raju, Raghavan; Lucas, Rudolf; Madaio, Michael P

2018-05-04

To investigate the role of protein kinase C-α (PKC-α) in glomerulonephritis, the capacity of PKC-α inhibition to reverse the course of established nephrotoxic nephritis (NTN) was evaluated. Nephritis was induced by a single injection of nephrotoxic serum and after its onset, a PKC-α inhibitor was administered either systemically or by targeted glomerular delivery. By day seven, all mice with NTN had severe nephritis, whereas mice that received PKC-α inhibitors in either form had minimal evidence of disease. To further understand the underlying mechanism, label-free shotgun proteomic analysis of the kidney cortexes were performed, using quantitative mass spectrometry. Ingenuity pathway analysis revealed 157 differentially expressed proteins and mitochondrial dysfunction as the most modulated pathway. Functional protein groups most affected by NTN were mitochondrial proteins associated with respiratory processes. These proteins were down-regulated in the mice with NTN, while their expression was restored with PKC-α inhibition. This suggests a role for proteins that regulate oxidative phosphorylation in recovery. In cultured glomerular endothelial cells, nephrotoxic serum caused a decrease in mitochondrial respiration and membrane potential, mitochondrial morphologic changes and an increase in glycolytic lactic acid production; all normalized by PKC-α inhibition. Thus, PKC-α has a critical role in NTN progression, and the results implicate mitochondrial processes through restoring oxidative phosphorylation, as an essential mechanism underlying recovery. Importantly, our study provides additional support for targeted therapy to glomeruli to reverse the course of progressive disease. Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Cyclooxygenase Inhibition in Sepsis: Is There Life after Death?

PubMed Central

Aronoff, David M.

2012-01-01

Prostaglandins are important mediators and modulators of the inflammatory response to infection. The prostaglandins participate in the pathogenesis of hemodynamic collapse, organ failure, and overwhelming inflammation that characterize severe sepsis and shock. In light of this, cyclooxygenase (COX) inhibiting pharmacological agents have been extensively studied for their capacity to ameliorate the aberrant physiological and immune responses during severe sepsis. Animal models of sepsis, using the systemic administration of pathogen-associated molecular patterns (PAMPs) or live pathogens, have been used to examine the effectiveness of COX inhibition as a treatment for severe sepsis. These studies have largely shown beneficial effects on mortality. However, human studies have failed to show clinical utility of COX inhibitor treatment in severely septic patients. Why this approach “worked” in animals but not in humans might reflect differences in the controlled nature of animal investigations compared to human studies. This paper contrasts the impact of COX inhibitors on mortality in animal models of sepsis and human studies of sepsis and examines potential reasons for differences between these two settings. PMID:22665954

Antifibrotic Mechanism of Pinocembrin: Impact on Oxidative Stress, Inflammation and TGF-β /Smad Inhibition in Rats.

PubMed

Said, Marwa M; Azab, Samar S; Saeed, Noha M; El-Demerdash, Ebtehal

2018-03-01

The present study aimed to elucidate the potential antifibrotic effects of pinocembrin (PIN), a flavanone found abundantly in honey and propolis, by studying its effect on different oxidative stress, inflammatory and fibrosis markers in an experimental model of CCl4-induced liver fibrosis. PIN (20 mg/kg) was given orally 3 times/week for 6 consecutive weeks alternating with CCl4 (0.5 mL/kg, 1:1 mixture with corn oil, i. p.) twice weekly. Different hepatotoxicity indices, oxidative stress, inflammatory and liver fibrosis markers were assessed. PIN significantly restored liver transaminases and total cholesterol to normal levels. Also, PIN ameliorated oxidative stress injury evoked by CCl4 as evidenced by inhibition of reduced glutathione depletion and lipid peroxidation as well as elevation of antioxidant enzyme superoxide dismutase (SOD). Further, PIN upregulated the nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), thereby inducing the expression and activity of the cytoprotective enzyme hemeoxygenase-1 (HO-1). Moreover, PIN alleviated pro-inflammatory cytokines such as TNF-α via inhibiting nuclear factor-κB (NF-κB) activation. As markers of fibrosis, collagen and α-SMA expression increased markedly in the CCl4 group and PIN prevented these alterations. In addition, PIN down-regulated TGFβ1 and p-Smad2/3, thereby inhibiting TGFβ1/Smad signaling pathway. These results suggest that PIN possess potent antifibrotic effects that can be explained on its antioxidant properties. It ameliorates oxidative stress and inflammation during induction of fibrogenesis via its ability to augment celular antioxidant defenses, activating Nrf2-mediated HO-1 expression and modulating NF-κB and TGF-β1/Smad signaling pathway.

Inhaled ENaC antisense oligonucleotide ameliorates cystic fibrosis-like lung disease in mice.

PubMed

Crosby, Jeff R; Zhao, Chenguang; Jiang, Chong; Bai, Dong; Katz, Melanie; Greenlee, Sarah; Kawabe, Hiroshi; McCaleb, Michael; Rotin, Daniela; Guo, Shuling; Monia, Brett P

2017-11-01

Epithelial sodium channel (ENaC, Scnn1) hyperactivity in the lung leads to airway surface dehydration and mucus accumulation in cystic fibrosis (CF) patients and in mice with CF-like lung disease. We identified several potent ENaC specific antisense oligonucleotides (ASOs) and tested them by inhalation in mouse models of CF-like lung disease. The inhaled ASOs distributed into lung airway epithelial cells and decreased ENaC expression by inducing RNase H1-dependent degradation of the targeted Scnn1a mRNA. Aerosol delivered ENaC ASO down-regulated mucus marker expression and ameliorated goblet cell metaplasia, inflammation, and airway hyper-responsiveness. Lack of systemic activity of ASOs delivered via the aerosol route ensures the safety of this approach. Our results demonstrate that antisense inhibition of ENaC in airway epithelial cells could be an effective and safe approach for the prevention and reversal of lung symptoms in CF and potentially other inflammatory diseases of the lung. Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Naja naja atra venom ameliorates pulmonary fibrosis by inhibiting inflammatory response and oxidative stress.

PubMed

Cui, Kui; Kou, Jian-Qun; Gu, Jin-Hua; Han, Rong; Wang, Guanghui; Zhen, Xuechu; Qin, Zheng-Hong

2014-12-02

Naja naja atra venom (NNAV) displays diverse pharmacological actions including analgesia, anti-inflammation and immune regulation.In this study, we investigated the effects of NNAV on pulmonary fibrosis and its mechanisms of action. To determine if Naja naja atra venom (NNAV) can produce beneficial effects on pulmonary fibrosis, two marine models of pulmonary fibrosis were produced with bleomycin (BLM) and lipopolysaccharide (LPS). NNAV (30, 90, 270 μg/kg) was orally administered once a day started five days before BLM and LPS until to the end of experiment. The effects of NNAV treatment on pulmonary injury were evaluated with arterial blood gas analysis, hydroxyproline (HYP) content assessment and HE/Masson staining. The effects of NNAV treatment on inflammatory related cytokines, fibrosis related TGF-β/Smad signaling pathway and oxidative stress were examined. The results showed that NNAV improved the lung gas-exchange function and attenuated the fibrotic lesions in lung. NNAV decreased IL-1β and TNF-α levels in serum in both pulmonary fibrosis models. NNAV inhibited the activation of NF-κB in LPS-induced and TGF-β/Smad pathway in BLM-induced pulmonary fibrosis. Additionally, NNAV also increased the levels of SOD and GSH and reduced the levels of MDA in BLM-induced pulmonary fibrosis model. The present study indicates that NNAV attenuates LPS- and BLM-induced lung fibrosis. Its mechanisms of action are associated with inhibiting inflammatory response and oxidative stress. The study suggests that NNAV might be a potential therapeutic drug for treatment of pulmonary fibrosis.

Cinnamon extract inhibits α-glucosidase activity and dampens postprandial glucose excursion in diabetic rats

PubMed Central

2011-01-01

Background α-glucosidase inhibitors regulate postprandial hyperglycemia (PPHG) by impeding the rate of carbohydrate digestion in the small intestine and thereby hampering the diet associated acute glucose excursion. PPHG is a major risk factor for diabetic vascular complications leading to disabilities and mortality in diabetics. Cinnamomum zeylanicum, a spice, has been used in traditional medicine for treating diabetes. In this study we have evaluated the α-glucosidase inhibitory potential of cinnamon extract to control postprandial blood glucose level in maltose, sucrose loaded STZ induced diabetic rats. Methods The methanol extract of cinnamon bark was prepared by Soxhlet extraction. Phytochemical analysis was performed to find the major class of compounds present in the extract. The inhibitory effect of cinnamon extract on yeast α-glucosidase and rat-intestinal α-glucosidase was determined in vitro and the kinetics of enzyme inhibition was studied. Dialysis experiment was performed to find the nature of the inhibition. Normal male Albino wistar rats and STZ induced diabetic rats were treated with cinnamon extract to find the effect of cinnamon on postprandial hyperglycemia after carbohydrate loading. Results Phytochemical analysis of the methanol extract displayed the presence of tannins, flavonoids, glycosides, terpenoids, coumarins and anthraquinones. In vitro studies had indicated dose-dependent inhibitory activity of cinnamon extract against yeast α-glucosidase with the IC 50 value of 5.83 μg/ml and mammalian α-glucosidase with IC 50 value of 670 μg/ml. Enzyme kinetics data fit to LB plot pointed out competitive mode of inhibition and the membrane dialysis experiment revealed reversible nature of inhibition. In vivo animal experiments are indicative of ameliorated postprandial hyperglycemia as the oral intake of the cinnamon extract (300 mg/kg body wt.) significantly dampened the postprandial hyperglycemia by 78.2% and 52.0% in maltose and sucrose

Bardoxolone-methyl inhibits migration and metabolism in MCF7 cells.

PubMed

Refaat, Alaa; Pararasa, Chathyan; Arif, Muhammed; Brown, James E P; Carmichael, Amtul; Ali, Sameh S; Sakurai, Hiroaki; Griffiths, Helen R

2017-02-01

Bardoxolone-methyl (BAR) is reported to have anti-inflammatory, anti-proliferative and anti-fibrotic effects. BAR activates Nrf2 and may ameliorate oxidative stress through induction of antioxidant genes. However, off-target effects, probably concentration and NFkB-dependent, have limited the clinical use of BAR. Nrf2 regulates expression of antioxidant and mitochondrial genes and has been proposed as a target for both obesity and breast cancer. Therefore, we explored whether BAR can alter migration and proliferation in the MCF7 cell line and whether metabolic function is affected by BAR. Incubation with BAR caused a time-dependent migratory inhibition and an associated decrease in mitochondrial respiration. Both migratory and mitochondrial inhibition by BAR were further enhanced in the presence of fatty acids. In addition to the activation of Nrf2, BAR altered the expression of target mRNA GCLC and UCP1. After 24 h, BAR inhibited both glycolytic capacity, reserve (p < 0.05) and oxidative phosphorylation (p < 0.001) with an associated increase in mitochondrial ROS and loss of intracellular glutathione in MCF7 cells; however, impairment of mitochondrial activity was prevented by N-acetyl cysteine. The fatty acid, palmitate, increased mitochondrial ROS, impaired migration and oxidative phosphorylation but palmitate toxicity towards MCF7 could not be inhibited by N-acetyl cysteine suggesting that they exert effects through different pathways. BAR-activated AKT, induced DNA damage and inhibited cell proliferation. When the proteasome was inhibited, there was loss of BAR-mediated changes in p65 phosphorylation and SOD2 expression suggesting non-canonical NFkB signaling effects. These data suggest that BAR-induced ROS are important in inhibiting MCF7 migration and metabolism by negatively affecting glycolytic capacity and mitochondrial function.

Curcumin ameliorates dopaminergic neuronal oxidative damage via activation of the Akt/Nrf2 pathway.

PubMed

Cui, Qunli; Li, Xin; Zhu, Hongcan

2016-02-01

Parkinson's disease (PD) is an age-related complex neurodegenerative disease that affects ≤ 80% of dopaminergic neurons in the substantia nigra pars compacta (SNpc). It has previously been suggested that mitochondrial dysfunction, oxidative stress and oxidative damage underlie the pathogenesis of PD. Curcumin, which is a major active polyphenol component extracted from the rhizomes of Curcuma longa (Zingiberaceae), has been reported to exert neuroprotective effects on an experimental model of PD. The present study conducted a series of in vivo experiments, in order to investigate the effects of curcumin on behavioral deficits, oxidative damage and related mechanisms. The results demonstrated that curcumin was able to significantly alleviate motor dysfunction and increase suppressed tyrosine hydroxylase (TH) activity in the SNpc of rotenone (ROT)-injured rats. Biochemical measurements indicated that rats pretreated with curcumin exhibited increased glutathione (GSH) levels, and reduced reactive oxygen species activity and malondialdehyde content. Mechanistic studies demonstrated that curcumin significantly restored the expression levels of heme oxygenase-1 and quinone oxidoreductase 1, thus ameliorating ROT-induced damage in vivo, via the phosphorylation of Akt and nuclear factor erythroid 2-related factor 2 (Nrf2). Further studies indicated that the Akt/Nrf2 signaling pathway was associated with the protective role of curcumin in ROT-treated rats. Inhibiting the Akt/Nrf2 pathway using a lentiviral vector containing Nrf2-specific short hairpin RNA, or the phosphoinositide 3-kinase inhibitor LY294002, markedly reduced the expression levels of TH and GSH, ultimately attenuating the neuroprotective effects of curcumin against oxidative damage. These results indicated that curcumin was able to significantly ameliorate ROT-induced dopaminergic neuronal oxidative damage in the SNpc of rats via activation of the Akt/Nrf2 signaling pathway.

Irisin protects against endothelial injury and ameliorates atherosclerosis in apolipoprotein E-Null diabetic mice.

PubMed

Lu, Junyan; Xiang, Guangda; Liu, Min; Mei, Wen; Xiang, Lin; Dong, Jing

2015-12-01

The circulating irisin increases energy expenditure and improves insulin resistance in mice and humans. The improvement of insulin resistance ameliorates atherosclerosis. Therefore, we hypothesized that irisin alleviates atherosclerosis in diabetes. Endothelial function was measured by acetylcholine-induced endothelium-dependent vasodilation using aortic rings in apolipoprotein E-Null (apoE(-/-)) streptozotocin-induced diabetic mice. Atherosclerotic lesion was evaluated by plaque area and inflammatory response in aortas. In addition, the endothelium-protective effects of irisin were also further investigated in primary human umbilical vein endothelial cells (HUVECs) in vitro. The in vivo experiments showed that irisin treatment significantly improved endothelial dysfunction, decreased endothelial apoptosis, and predominantly decreased atherosclerotic plaque area of both en face and cross sections when compared with normal saline-treated diabetic mice. Moreover, the infiltrating macrophages and T lymphocytes within plaque and the mRNA expression levels of inflammatory cytokines in aortas were also significantly reduced by irisin treatment in mice. The in vitro experiments revealed that irisin inhibited high glucose-induced apoptosis, oxidative stress and increased antioxidant enzymes expression in HUVECs, and pretreatment with LY294002, l-NAME, AMPK-siRNA or eNOS-siRNA, attenuated the protection of irisin on HUVECs apoptosis induced by high glucose. In addition, the in vivo and in vitro experiments showed that irisin increased the phosphorylation of AMPK, Akt and eNOS in aortas and cultured HUVECs. The present study indicates that systemic administration of irisin may be protected against endothelial injury and ameliorated atherosclerosis in apoE(-/-) diabetic mice. The endothelium-protective action of irisin was through activation of AMPK-PI3K-Akt-eNOS signaling pathway. Irisin could be therapeutic for atherosclerotic vascular diseases in diabetes. Copyright �

Amelioration of ethionine toxicity in the chick.

PubMed

Lowry, K R; Baker, D H

1987-06-01

Several chick bioassays were conducted to evaluate means of ameliorating ethionine toxicity. Supplementing a corn-soy diet marginally deficient in sulfur amino acids (methionine + cystine) with .075% D,L-ethionine reduced weight gain in 8-day-old chicks by 70% compared to gains of unsupplemented controls. Dietary addition of .50% DL-methionine prevented reduction in weight gain and feed intake resulting from ethionine supplementation whereas feeding supplemental L-cystine was without effect. Supplementation of the ethionine-containing diet with either choline or betaine ameliorated the growth depression, although neither compound was able to completely overcome the toxic effects of ethionine. Dietary ethionine did not affect plasma levels of free methionine or cystine but did increase plasma free glycine 6-fold. Dietary addition of .50% DL-methionine caused normalization of plasma glycine levels whereas it elevated plasma methionine concentration. Although results suggested the possibility of ethionine-induced serine or threonine deficiency, dietary additions of .75% L-serine or .75% L-threonine failed to improve chick weight gain. These studies suggest that ethionine, in addition to affecting transsulfuration and transmethylation activity may exert specific effects on certain amino acids in tissue pools.

Monosialotetrahexosylganglioside Inhibits the Expression of p-CREB and NR2B in the Auditory Cortex in Rats with Salicylate-Induced Tinnitus.

PubMed

Song, Rui-Biao; Lou, Wei-Hua

2015-01-01

This study investigated the effects of monosialotetrahexosylganglioside (GM1) on the expression of N-methyl-D-aspartate receptor subunit 2B (NR2B) and phosphorylated (p)-cyclic AMP response element-binding protein (CREB) in the auditory cortex of rats with tinnitus. Tinnitus-like behavior in rats was tested with the gap prepulse inhibition of acoustic startle paradigm. We then investigated the NR2B mRNA and protein and p-CREB protein levels in the auditory cortex of tinnitus rats compared with normal rats. Rats treated for 4 days with salicylate exhibited tinnitus. NR2B mRNA and protein and p-CREB protein levels were upregulated in these animals, with expression returning to normal levels 14 days after cessation of treatment; baseline levels of NR2B and p-CREB were also restored by GM1 administration. These data suggest that chronic salicylate administration induces tinnitus via upregulation of p-CREB and NR2B expression, and that GM1 can potentially be used to treat tinnitus.

Fibroblast growth factor receptor signaling affects development and function of dopamine neurons - inhibition results in a schizophrenia-like syndrome in transgenic mice.

PubMed

Klejbor, Ilona; Myers, Jason M; Hausknecht, Kathy; Corso, Thomas D; Gambino, Angelo S; Morys, Janusz; Maher, Pamela A; Hard, Robert; Richards, Jerry; Stachowiak, Ewa K; Stachowiak, Michal K

2006-06-01

Developing and mature midbrain dopamine (DA) neurons express fibroblast growth factor (FGF) receptor-1 (FGFR1). To determine the role of FGFR1 signaling in the development of DA neurons, we generated transgenic mice expressing a dominant negative mutant [FGFR1(TK-)] from the catecholaminergic, neuron-specific tyrosine hydroxylase (TH) gene promoter. In homozygous th(tk-)/th(tk-) mice, significant reductions in the size of TH-immunoreactive neurons were found in the substantia nigra compacta (SNc) and the ventral tegmental area (VTA) at postnatal days 0 and 360. Newborn th(tk-)/th(tk-) mice had a reduced density of DA neurons in both SNc and VTA, and the changes in SNc were maintained into adulthood. The reduced density of DA transporter in the striatum further demonstrated an impaired development of the nigro-striatal DA system. Paradoxically, the th(tk-)/th(tk-) mice had increased levels of DA, homovanilic acid and 3-methoxytyramine in the striatum, indicative of excessive DA transmission. These structural and biochemical changes in DA neurons are similar to those reported in human patients with schizophrenia and, furthermore, these th(tk-)/th(tk-) mice displayed an impaired prepulse inhibition that was reversed by a DA receptor antagonist. Thus, this study establishes a new developmental model for a schizophrenia-like disorder in which the inhibition of FGF signaling leads to alterations in DA neurons and DA-mediated behavior.

DOT1L inhibition attenuates graft-versus-host disease by allogeneic T cells in adoptive immunotherapy models.

PubMed

Kagoya, Yuki; Nakatsugawa, Munehide; Saso, Kayoko; Guo, Tingxi; Anczurowski, Mark; Wang, Chung-Hsi; Butler, Marcus O; Arrowsmith, Cheryl H; Hirano, Naoto

2018-05-15

Adoptive T-cell therapy is a promising therapeutic approach for cancer patients. The use of allogeneic T-cell grafts will improve its applicability and versatility provided that inherent allogeneic responses are controlled. T-cell activation is finely regulated by multiple signaling molecules that are transcriptionally controlled by epigenetic mechanisms. Here we report that inhibiting DOT1L, a histone H3-lysine 79 methyltransferase, alleviates allogeneic T-cell responses. DOT1L inhibition reduces miR-181a expression, which in turn increases the ERK phosphatase DUSP6 expression and selectively ameliorates low-avidity T-cell responses through globally suppressing T-cell activation-induced gene expression alterations. The inhibition of DOT1L or DUSP6 overexpression in T cells attenuates the development of graft-versus-host disease, while retaining potent antitumor activity in xenogeneic and allogeneic adoptive immunotherapy models. These results suggest that DOT1L inhibition may enable the safe and effective use of allogeneic antitumor T cells by suppressing unwanted immunological reactions in adoptive immunotherapy.

Novel inhibitor candidates of TRPV2 prevent damage of dystrophic myocytes and ameliorate against dilated cardiomyopathy in a hamster model.

PubMed

Iwata, Yuko; Katayama, Yoshimi; Okuno, Yasushi; Wakabayashi, Shigeo

2018-03-06

Transient receptor potential cation channel, subfamily V, member 2 (TRPV2) is a principal candidate for abnormal Ca 2+ -entry pathways, which is a potential target for therapy of muscular dystrophy and cardiomyopathy. Here, an in silico drug screening and the following cell-based screening to measure the TRPV2 activation were carried out in HEK293 cells expressing TRPV2 using lead compounds (tranilast or SKF96365) and off-patent drug stocks. We identified 4 chemical compounds containing amino-benzoyl groups and 1 compound (lumin) containing an ethylquinolinium group as candidate TRPV2 inhibitors. Three of these compounds inhibited Ca 2+ entry through both mouse and human TRPV2, with IC 50 of less than 10 μM, but had no apparent effect on other members of TRP family such as TRPV1 and TRPC1. Particularly, lumin inhibited agonist-induced TRPV2 channel activity at a low dose. These compounds inhibited abnormally increased Ca 2+ influx and prevented stretch-induced skeletal muscle damage in cultured myocytes from dystrophic hamsters (J2N-k). Further, they ameliorated cardiac dysfunction, and prevented disease progression in vivo in the same J2N-k hamsters developing dilated cardiomyopathy as well as muscular dystrophy. The identified compounds described here are available as experimental tools and represent potential treatments for patients with cardiomyopathy and muscular dystrophy.

Novel inhibitor candidates of TRPV2 prevent damage of dystrophic myocytes and ameliorate against dilated cardiomyopathy in a hamster model

PubMed Central

Iwata, Yuko; Katayama, Yoshimi; Okuno, Yasushi; Wakabayashi, Shigeo

2018-01-01

Transient receptor potential cation channel, subfamily V, member 2 (TRPV2) is a principal candidate for abnormal Ca2+-entry pathways, which is a potential target for therapy of muscular dystrophy and cardiomyopathy. Here, an in silico drug screening and the following cell-based screening to measure the TRPV2 activation were carried out in HEK293 cells expressing TRPV2 using lead compounds (tranilast or SKF96365) and off-patent drug stocks. We identified 4 chemical compounds containing amino-benzoyl groups and 1 compound (lumin) containing an ethylquinolinium group as candidate TRPV2 inhibitors. Three of these compounds inhibited Ca2+ entry through both mouse and human TRPV2, with IC50 of less than 10 μM, but had no apparent effect on other members of TRP family such as TRPV1 and TRPC1. Particularly, lumin inhibited agonist-induced TRPV2 channel activity at a low dose. These compounds inhibited abnormally increased Ca2+ influx and prevented stretch-induced skeletal muscle damage in cultured myocytes from dystrophic hamsters (J2N-k). Further, they ameliorated cardiac dysfunction, and prevented disease progression in vivo in the same J2N-k hamsters developing dilated cardiomyopathy as well as muscular dystrophy. The identified compounds described here are available as experimental tools and represent potential treatments for patients with cardiomyopathy and muscular dystrophy. PMID:29581825

RNCR3 knockdown inhibits diabetes mellitus-induced retinal reactive gliosis

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

Liu, Chang; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing

Retinal reactive gliosis is an important pathological feature of diabetic retinopathy. Identifying the underlying mechanisms causing reactive gliosis will be important for developing new therapeutic strategies for treating diabetic retinopathy. Herein, we show that long noncoding RNA-RNCR3 knockdown significantly inhibits retinal reactive gliosis. RNCR3 knockdown leads to a marked reduction in the release of several cytokines. RNCR3 knockdown alleviates diabetes mellitus-induced retinal neurodegeneration, as shown by less apoptotic retinal cells and ameliorative visual function. RNCR3 knockdown could also decrease Müller glial cell viability and proliferation, and reduce the expression of glial reactivity-related genes including GFAP and vimentin in vitro. Collectively, thismore » study shows that RNCR3 knockdown may be a promising strategy for the prevention of diabetes mellitus-induced retinal neurodegeneration. - Highlights: • RNCR3 knockdown inhibits retinal reactive gliosis. • RNCR3 knockdown causes a significant change in cytokine profile. • RNCR3 knockdown alleviates diabetes mellitus-induced retinal neurodegeneration. • RNCR3 knockdown affects Müller glial cell function in vitro.« less

Recombinant mouse periostin ameliorates coronal sutures fusion in Twist1+/- mice.

PubMed

Bai, Shanshan; Li, Dong; Xu, Liang; Duan, Huichuan; Yuan, Jie; Wei, Min

2018-04-17

Saethre-Chotzen syndrome is an autosomal dominantly inherited disorder caused by mutations in the twist family basic helix-loop-helix transcription factor 1 (TWIST1) gene. Surgical procedures are frequently required to reduce morphological and functional defects in patients with Saethre-Chotzen syndrome. Therefore, the development of noninvasive procedures to treat Saethre-Chotzen syndrome is critical. We identified that periostin, which is an extracellular matrix protein that plays an important role in both bone and connective tissues, is downregulated in craniosynostosis patients. We aimed to verify the effects of different concentrations (0, 50, 100, and 200 μg/l) of recombinant mouse periostin in Twist1 +/- mice (a mouse model of Saethre-Chotzen syndrome) coronal suture cells in vitro and in vivo. Cell proliferation, migration, and osteogenic differentiation were observed and detected. Twist1 +/- mice were also injected with recombinant mouse periostin to verify the treatment effects. Cell Counting Kit-8 results showed that recombinant mouse periostin inhibited the proliferation of suture-derived cells in a time- and concentration-dependent manner. Cell migration was also suppressed when treated with recombinant mouse periostin. Real-time quantitative PCR and Western blotting results suggested that messenger ribonucleic acid and protein expression of alkaline phosphatase, bone sialoprotein, collagen type I, and osteocalcin were all downregulated after treatment with recombinant mouse periostin. However, the expression of Wnt-3a, Wnt-1, and β-catenin were upregulated. The in vivo results demonstrated that periostin-treated Twist1 +/- mice showed patent coronal sutures in comparison with non-treated Twist1 +/- mice which have coronal craniosynostosis. Our results suggest that recombinant mouse periostin can inhibit coronal suture cell proliferation and migration and suppress osteogenic differentiation of suture-derived cells via Wnt canonical signaling, as

Valsartan ameliorates podocyte loss in diabetic mice through the Notch pathway.

PubMed

Gao, Feng; Yao, Min; Cao, Yanping; Liu, Shuxia; Liu, Qingjuan; Duan, Huijun

2016-05-01

The Notch pathway is known to be linked to diabetic nephropathy (DN); however, its underlying mechanism was poorly understood. In the present study, we examined the effect of Valsartan, an angiotensin II type 1 receptor antagonist, on the Notch pathway and podocyte loss in DN. Diabetes was induced in mice by an intraperitoneal injection of streptozotocin and and this was followed by treatment with Valsartan. Levels of blood glucose, kidney weight and body weight, as well as proteinuria were measured. Samples of the kidneys were also histologically examined. The relative levels of Jagged1, Notch1, Notch intracellular domain 1 (NICD1), Hes family BHLH transcription factor 1 (Hes1) and Hes-related family BHLH transcription factor with YRPW motif 1 expression (Hey1) in the glomeruli were determined by immunohistochemical analysis, western blot analysis and RT-qPCR. The B-Cell CLL/Lymphoma 2 (Bcl-2) and p53 pathways were examined by western blot analysis. Apoptosis and detachment of podocytes from the glomerular basement membrane were examined using a TUNEL assay, flow cytometric analysis and ELISA. The number of podocytes was quantified by measuring Wilms tumor-1 (WT-1) staining. We noted that the expression of Jagged1, Notch1, NICD1, Hes1 and Hey1 was increased in a time-dependent manner in the glomeruli of mice with streptozotocin (STZ)-induced diabetes. Moreover, in diabetic mice, Valsartan significantly reduced kidney weight and proteinuria, and mitigated the pathogenic processes in the kidneys. Valsartan also inhibited the activation of Notch, Bcl-2 and p53 pathways and ameliorated podocyte loss in the glomeruli of mice with STZ-induced diabetes. Taken together, these findings indicated that Valsartan exerted a beneficial effect on reducing podocyte loss, which is associated with inhibition of Notch pathway activation in the glomeruli of diabetic mice.

Ferulic acid ameliorates TNBS-induced ulcerative colitis through modulation of cytokines, oxidative stress, iNOs, COX-2, and apoptosis in laboratory rats

PubMed Central

Sadar, Smeeta S.; Vyawahare, Niraj S.; Bodhankar, Subhash L.

2016-01-01

Ulcerative colitis (UC) is a chronic immune-inflammatory disorder characterized by oxido-nitrosative stress, the release of pro-inflammatory cytokines and apoptosis. Ferulic acid (FA), a phenolic compound is considered to possess potent antioxidant, anti-apoptotic and anti-inflammatory activities. The aim is to evaluate possible mechanism of action of FA against trinitrobenzensulfonic acid (TNBS) induced ulcerative colitis (UC) in rats. UC was induced in Sprague-Dawley rats (150-200 g) by intrarectal administration of TNBS (100 mg/kg). FA was administered (10, 20 and 40 mg/kg, p.o.) for 14 days after colitis was induced. Various biochemical, molecular and histological changes were assessed in the colon. Intrarectal administration of TNBS caused significant induction of ulcer in the colon with an elevation of oxido-nitrosative stress, myeloperoxidase and hydroxyproline activity in the colon. Administration of FA (20 and 40 mg/kg) significantly decrease oxido-nitrosative stress, myeloperoxidase, and hydroxyproline activities. Up-regulated mRNA expression of TNF-α, IL-1β, IL-6, COX-2, and iNOs, as well as down-regulated IL-10 mRNA expressions after TNBS administration, were significantly inhibited by FA (20 and 40 mg/kg) treatment. Flow cytometric analysis revealed that intrarectal administration of TNBS-induced significantly enhanced the colonic apoptosis whereas administration of FA (20 and 40 mg/kg) significantly restored the elevated apoptosis. FA administration also significantly restored the histopathological aberration induced by TNBS. The findings of the present study demonstrated that FA ameliorates TNBS-induced colitis via inhibition of oxido-nitrosative stress, apoptosis, proinflammatory cytokines production, and down- regulation of COX-2 synthesis. Graphical Abstract: TNBS caused activation of T cells which interact with CD40 on antigen presenting cells i.e. dendritic cells (DC) that induce the key Interleukin 12 (IL-12)-mediated Th1 T cell immune

Sildenafil ameliorates right ventricular early molecular derangement during left ventricular pressure overload.

PubMed

Imai, Yousuke; Kariya, Taro; Iwakiri, Masaki; Yamada, Yoshitsugu; Takimoto, Eiki

2018-01-01

Right ventricular (RV) dysfunction following left ventricular (LV) failure is associated with poor prognosis. RV remodeling is thought initiated by the increase in the afterload of RV due to secondary pulmonary hypertension (PH) to impaired LV function; however, RV molecular changes might occur in earlier stages of the disease. cGMP (cyclic guanosine monophosphate)-phosphodiesterase 5 (PDE5) inhibitors, widely used to treat PH through their pulmonary vasorelaxation properties, have shown direct cardiac benefits, but their impacts on the RV in LV diseases are not fully determined. Here we show that RV molecular alterations occur early in the absence of RV hemodynamic changes during LV pressure-overload and are ameliorated by PDE5 inhibition. Two-day moderate LV pressure-overload (transverse aortic constriction) neither altered RV pressure/ function nor RV weight in mice, while it induced only mild LV hypertrophy. Importantly, pathological molecular features were already induced in the RV free wall myocardium, including up-regulation of gene markers for hypertrophy and inflammation, and activation of extracellular signal-regulated kinase (ERK) and calcineurin. Concomitant PDE5 inhibition (sildenafil) prevented induction of such pathological genes and activation of ERK and calcineurin in the RV as well as in the LV. Importantly, dexamethasone also prevented these RV molecular changes, similarly to sildenafil treatment. These results suggest the contributory role of inflammation to the early pathological interventricular interaction between RV and LV. The current study provides the first evidence for the novel early molecular cross-talk between RV and LV, preceding RV hemodynamic changes in LV disease, and supports the therapeutic strategy of enhancing cGMP signaling pathway to treat heart diseases.

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

PubMed

Kumari, Mrinalini; Singh, Poonam

2015-01-01

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. 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. 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. The fruit extract of TT ameliorates the MTZ-induced alterations in the testis.

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

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.

Amelioration of nickel phytotoxicity in muck and mineral soils.

PubMed

Kukier, U; Chaney, R L

2001-01-01

In situ remediation (phytostabilization) is a cost-effective solution for restoring the productivity of metal-contaminated soils and protection of food chains. A pot experiment with wheat (Triticum aestivum L.), oat (Avena sativa L.), and redbeet (Beta vulgaris L.) was conducted to test the ability of limestone and hydrous ferric oxide (HFO) to ameliorate Ni phytotoxicity in two soils contaminated by particulate emissions from a nickel refinery. Quarry muck (Terric Haplohemist; 72% organic matter) contained 2210 mg kg(-1) of total Ni. The mineral soil, Welland silt loam (Typic Epiaquoll), was more contaminated (2930 mg Ni kg(-1)). Both soils were very strongly acidic, allowing the soil Ni to be soluble and phytotoxic. Nickel phytotoxicity of the untreated muck soil was not very pronounced and could be easily confused with symptoms of Mn deficiency that occurred in this soil even with Mn fertilization. Severe nickel phytotoxicity of the untreated mineral soil prevented any growth of redbeet, the most sensitive crop; even wheat, a relatively Ni-resistant species, was severely damaged. White banding indicative of Ni phytotoxicity was present on oat and wheat leaves grown on the acidic mineral soil. Soil Ni extracted with diethylenetriaminepentaacetic acid (DTPA) and 0.01 M Sr(NO3)2 was indicative of the ameliorative effect of amendments and correlated well with Ni concentrations in plant shoots. Making soils calcareous was an effective treatment to reduce plant-available Ni and remediate Ni phytotoxicity of these soils to all crops tested. The ameliorative effect of HFO was crop-specific and much less pronounced.

Stevioside ameliorates high-fat diet-induced insulin resistance and adipose tissue inflammation by downregulating the NF-{kappa}B pathway

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

Wang, Zhiquan; Xue, Liqiong; Guo, Cuicui

Highlights: Black-Right-Pointing-Pointer Stevioside ameliorates high-fat diet-induced insulin resistance. Black-Right-Pointing-Pointer Stevioside alleviates the adipose tissue inflammation. Black-Right-Pointing-Pointer Stevioside reduces macrophages infiltration into the adipose tissue. Black-Right-Pointing-Pointer Stevioside suppresses the activation of NF-{kappa}B in the adipose tissue. -- Abstract: Accumulating evidence suggests that adipose tissue is the main source of pro-inflammatory molecules that predispose individuals to insulin resistance. Stevioside (SVS) is a widely used sweetener with multiple beneficial effects for diabetic patients. In this study, we investigated the effect of SVS on insulin resistance and the pro-inflammatory state of adipose tissue in mice fed with a high-fat diet (HFD). Oral administration ofmore » SVS for 1 month had no effect on body weight, but it significantly improved fasting glucose, basal insulin levels, glucose tolerance and whole body insulin sensitivity. Interestingly, these changes were accompanied with decreased expression levels of several inflammatory cytokines in adipose tissue, including TNF-{alpha}, IL6, IL10, IL1{beta}, KC, MIP-1{alpha}, CD11b and CD14. Moreover, macrophage infiltration in adipose tissue was remarkably reduced by SVS. Finally, SVS significantly suppressed the nuclear factor-kappa b (NF-{kappa}B) signaling pathway in adipose tissue. Collectively, these results suggested that SVS may ameliorate insulin resistance in HFD-fed mice by attenuating adipose tissue inflammation and inhibiting the NF-{kappa}B pathway.« less

Enhanced Production of Adenosine Triphosphate by Pharmacological Activation of Adenosine Monophosphate-Activated Protein Kinase Ameliorates Acetaminophen-Induced Liver Injury.

PubMed

Hwang, Jung Hwan; Kim, Yong-Hoon; Noh, Jung-Ran; Choi, Dong-Hee; Kim, Kyoung-Shim; Lee, Chul-Ho

2015-10-01

The hepatic cell death induced by acetaminophen (APAP) is closely related to cellular adenosine triphosphate (ATP) depletion, which is mainly caused by mitochondrial dysfunction. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key sensor of low energy status. AMPK regulates metabolic homeostasis by stimulating catabolic metabolism and suppressing anabolic pathways to increase cellular energy levels. We found that the decrease in active phosphorylation of AMPK in response to APAP correlates with decreased ATP levels, in vivo. Therefore, we hypothesized that the enhanced production of ATP via AMPK stimulation can lead to amelioration of APAP-induced liver failure. A769662, an allosteric activator of AMPK, produced a strong synergistic effect on AMPK Thr172 phosphorylation with APAP in primary hepatocytes and liver tissue. Interestingly, activation of AMPK by A769662 ameliorated the APAP-induced hepatotoxicity in C57BL/6N mice treated with APAP at a dose of 400 mg/kg intraperitoneally. However, mice treated with APAP alone developed massive centrilobular necrosis, and APAP increased their serum alanine aminotransferase and aspartate aminotransferase levels. Furthermore, A769662 administration prevented the loss of intracellular ATP without interfering with the APAP-mediated reduction of mitochondrial dysfunction. In contrast, inhibition of glycolysis by 2-deoxy-glucose eliminated the beneficial effects of A769662 on APAP-mediated liver injury. In conclusion, A769662 can effectively protect mice against APAP-induced liver injury through ATP synthesis by anaerobic glycolysis. Furthermore, stimulation of AMPK may have potential therapeutic application for APAP overdose.

Amelioration of acidic soil increases the toxicity of the weak base carbendazim to the earthworm Eisenia fetida.

PubMed

Liu, Kailin; Wang, Shaoyun; Luo, Kun; Liu, Xiangying; Yu, Yunlong

2013-12-01

Ameliorating acidic soils is a common practice and may affect the bioavailability of an ionizable organic pollutant to organisms. The toxicity of the weak base carbendazim to the earthworm (Eisenia fetida) was studied in an acidic soil (pH-H₂O, 4.6) and in the ameliorated soil (pH-H₂O, 7.5). The results indicated that the median lethal concentration of carbendazim for E. fetida decreased from 21.8 mg/kg in acidic soil to 7.35 mg/kg in the ameliorated soil. To understand why the amelioration increased carbendazim toxicity to the earthworm, the authors measured the carbendazim concentrations in the soil porewater. The authors found increased carbendazim concentrations in porewater, resulting in increased toxicity of carbendazim to earthworms. The increased pore concentrations result from decreased adsorption because of the effects of pH and calcium ions. © 2013 SETAC.

Mangiferin ameliorates fatty liver via modulation of autophagy and inflammation in high-fat-diet induced mice.

PubMed

Wang, Hu; Zhu, Yang-Yang; Wang, Li; Teng, Tian; Zhou, Meng; Wang, Shu-Guang; Tian, Yi-Zhu; Du, Lei; Yin, Xiao-Xing; Sun, Ying

2017-12-01

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease globally. The progression of NAFLD is complex and associated with inflammation, oxidative stress, autophagy, endoplasmic reticulum stress, and insulin resistance. Mangiferin, a natural C-glucosyl xanthone, has been reported to show multiple biological activities. The aim of this study was to investigate the therapeutic effect of mangiferin on NAFLD and the underlying molecular mechanism. We established a mouse model of NAFLD using a high-fat diet (HFD), and injected the mice with different doses of mangiferin (15, 30, and 60mg/kg, intraperitoneal) for 12 weeks. Liver tissue was assessed to evaluate changes in inflammatory responses, autophagy, and glycolipid metabolism. We found that mangiferin decreased body weight, as well as the levels of triglycerides and total cholesterol in plasma and the liver. It also increased glucose tolerance in HFD-fed mice. In addition, mangiferin decreased inflammatory responses by inhibiting the activities of nuclear factor kappa B and c-Jun N-terminal kinase, regulated autophagy via the AMP-activated protein kinase/mechanistic target of rapamycin signaling pathway, and improved glycolipid metabolism via modulation of the insulin receptor substrate/phosphoinositide 3-kinase/protein kinase B signaling pathway. This study demonstrated that mangiferin significantly ameliorates NAFLD development in HFD-fed mice by inhibiting inflammatory responses, activating autophagy, and improving glycolipid metabolism. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Rebamipide ameliorates radiation-induced intestinal injury in a mouse model.

PubMed

Shim, Sehwan; Jang, Hyo-Sun; Myung, Hyun-Wook; Myung, Jae Kyung; Kang, Jin-Kyu; Kim, Min-Jung; Lee, Seung Bum; Jang, Won-Suk; Lee, Sun-Joo; Jin, Young-Woo; Lee, Seung-Sook; Park, Sunhoo

2017-08-15

Radiation-induced enteritis is a major side effect in cancer patients undergoing abdominopelvic radiotherapy. Radiation exposure produces an uncontrolled inflammatory cascade and epithelial cell loss leading to impaired epithelial barrier function. The goal of this study was to determine the effect of rebamipide on regeneration of the intestinal epithelia after radiation injury. The abdomens of C57BL/6 mice were exposed to 13Gy of irradiation (IR) and then the mice were treated with rebamipide. Upon IR, intestinal epithelia were destroyed structurally at the microscopic level and bacterial translocation was increased. The intestinal damage reached a maximum level on day 6 post-IR and intestinal regeneration occurred thereafter. We found that rebamipide significantly ameliorated radiation-induced intestinal injury. In mice treated with rebamipide after IR, intestinal barrier function recovered and expression of the tight junction components of the intestinal barrier were upregulated. Rebamipide administration reduced radiation-induced intestinal mucosal injury. The levels of proinflammatory cytokines and matrix metallopeptidase 9 (MMP9) were significantly reduced upon rebamipide administration. Intestinal cell proliferation and β-catenin expression also increased upon rebamipide administration. These data demonstrate that rebamipide reverses impairment of the intestinal barrier by increasing intestinal cell proliferation and attenuating the inflammatory response by inhibiting MMP9 and proinflammatory cytokine expression in a murine model of radiation-induced enteritis. Copyright © 2017 Elsevier Inc. All rights reserved.

Edaravone ameliorates compression-induced damage in rat nucleus pulposus cells.

PubMed

Lin, Hui; Ma, Xuan; Wang, Bai-Chuan; Zhao, Lei; Liu, Jian-Xiang; Pu, Fei-Fei; Hu, Yi-Qiang; Hu, Hong-Zhi; Shao, Zeng-Wu

2017-11-15

Edaravone is a strong free radical scavenger most used for treating acute ischemic stroke. In this study we investigated the protective effects and underlying mechanisms of edaravone on compression-induced damage in rat nucleus pulposus (NP) cells. Cell viability was determined using MTT assay methods. NP cell apoptosis was measured by Hoechst 33,258 staining and Annexin V/PI double staining. Intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and intracellular calcium ([Ca 2+ ] i ) were determined by fluorescent probes DCFH-DA, JC-1 and Fluo-3/AM, respectively. Apoptosis-related proteins (cleaved caspase-3, cytosolic cytochrome c, Bax and Bcl-2) and extracellular matrix proteins (aggrecan and collagen II) were analyzed by western blot. Edaravone attenuated the compression-induced decrease in viability of NP cells in a dose-dependent manner. 33,258 and Annexin V/PI double staining showed that edaravone protected NP cells from compression-induced apoptosis. Further studies confirmed that edaravone protected NP cells against compression-induced mitochondrial pathway of apoptosis by inhibiting overproduction of ROS, collapse of MMP and overload of [Ca 2+ ] i . In addition, edaravone promoted the expression of aggrecan and collagen II in compression-treated NP cells. These results strongly indicate that edaravone ameliorates compression-induced damage in rat nucleus pulposus cells. Edaravone could be a potential new drug for treatment of IDD. Copyright © 2017 Elsevier Inc. All rights reserved.

The effectiveness of surface liming in ameliorating the phytotoxic effects of soil contaminated by copper acid leach pad solution in an arid ecosystem

NASA Astrophysics Data System (ADS)

Golos, Peter

2016-04-01

Revegetation of sites following soil contamination can be challenging especially in identifying the most effective method for ameliorating phytotoxic effects in arid ecosystems. This study at a copper mine in the Great Sandy Desert of Western Australia investigated vegetation restoration of a site contaminated by acid (H2SO4) leach pad solution. Elevated soil copper at low soil pH is phytotoxic to plant roots inhibiting root elongation. In arid ecosystems where rapid root growth is crucial for seedling survival post germination physical or chemical barriers to root growth need to be identified and ameliorated. Initial attempt at rehabilitation of contaminated site with hydrated lime (CaOH2) at 2 tonnes/ha followed by ripping to 30 cm depth then seeding was ineffective as successful seedling emergence was followed by over 90% seedling mortality which was 10-fold greater than seedling mortality in an uncontaminated reference site. High mortality was attributed to seedling roots being impededed as soil water was more than 3-fold greater at 5 to 40 cm depth in contaminated site than reference site. In response to high seedling mortality after emergence test pits were dug to 1 m deep to collect soil samples at 10 cm intervals for phytotoxicity testing and to measure soil pH-CaCl2, copper (DPTA ion extraction), electrical conductivity and gravimetric water content in three replicate pits at three replicate sites. Also, soil impedance was measured down the soil profile at 5 cm intervals at six replicate points/pit. For phytotoxicity testing soil samples were placed into three replicate plastic pots/sample and seeded with 10 seeds of Avena sativa and watered daily. Seedlings were harvested after at least two weeks after seedling emergence and rooting depth in pots measured. There was no difference in seedling emergence and survival of seedlings between contaminated and uncontaminated soil samples however mean seedling root growth was significantly lower in soil samples

Ibrutinib treatment ameliorates murine chronic graft-versus-host disease

PubMed Central

Dubovsky, Jason A.; Flynn, Ryan; Du, Jing; Harrington, Bonnie K.; Zhong, Yiming; Kaffenberger, Benjamin; Yang, Carrie; Towns, William H.; Lehman, Amy; Johnson, Amy J.; Muthusamy, Natarajan; Devine, Steven M.; Jaglowski, Samantha; Serody, Jonathan S.; Murphy, William J.; Munn, David H.; Luznik, Leo; Hill, Geoffrey R.; Wong, Henry K.; MacDonald, Kelli K.P.; Maillard, Ivan; Koreth, John; Elias, Laurence; Cutler, Corey; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome; Panoskaltsis-Mortari, Angela; Byrd, John C.; Blazar, Bruce R.

2014-01-01

Chronic graft-versus-host disease (cGVHD) is a life-threatening impediment to allogeneic hematopoietic stem cell transplantation, and current therapies do not completely prevent and/or treat cGVHD. CD4+ T cells and B cells mediate cGVHD; therefore, targeting these populations may inhibit cGVHD pathogenesis. Ibrutinib is an FDA-approved irreversible inhibitor of Bruton’s tyrosine kinase (BTK) and IL-2 inducible T cell kinase (ITK) that targets Th2 cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity. Here, we evaluated whether ibrutinib could reverse established cGVHD in 2 complementary murine models, a model interrogating T cell–driven sclerodermatous cGVHD and an alloantibody-driven multiorgan system cGVHD model that induces bronchiolar obliterans (BO). In the T cell–mediated sclerodermatous cGVHD model, ibrutinib treatment delayed progression, improved survival, and ameliorated clinical and pathological manifestations. In the alloantibody-driven cGVHD model, ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Furthermore, ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD. Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent, warranting consideration for cGVHD clinical trials. PMID:25271622

Blockade of store-operated calcium entry alleviates high glucose-induced neurotoxicity via inhibiting apoptosis in rat neurons.

PubMed

Xu, Zhenkuan; Xu, Wenzhe; Song, Yan; Zhang, Bin; Li, Feng; Liu, Yuguang

2016-07-25

Altered store-operated calcium entry (SOCE) has been suggested to be involved in many diabetic complications. However, the association of altered SOCE and diabetic neuronal damage remains unclear. This study aimed to investigate the effects of altered SOCE on primary cultured rat neuron injury induced by high glucose. Our data demonstrated that high glucose increased rat neuron injury and upregulated the expression of store-operated calcium channel (SOC). Inhibition of SOCE by a pharmacological inhibitor and siRNA knockdown of stromal interaction molecule 1 weakened the intracellular calcium overload, restored mitochondrial membrane potential, downregulated cytochrome C release and inhibited cell apoptosis. As well, treatment with the calcium chelator BAPTA-AM prevented cell apoptosis by ameliorating the high glucose-increased intracellular calcium level. These findings suggest that SOCE blockade may alleviate high glucose-induced neuronal damage by inhibiting apoptosis. SOCE might be a promising therapeutic target in diabetic neurotoxicity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Ginger and alpha lipoic acid ameliorate age-related ultrastructural changes in rat liver.

PubMed

Mahmoud, Y I; Hegazy, H G

2016-01-01

Because of the important role that oxidative stress is thought to play in the aging process, antioxidants could be candidates for preventing its related pathologies. We investigated the ameliorative effects of two antioxidant supplements, ginger and alpha lipoic acid (ALA), on hepatic ultrastructural alterations in old rats. Livers of young (4 months) and old (24 months) Wistar rats were studied using transmission electron microscopy. Livers of old rats showed sinusoidal collapse and congestion, endothelial thickening and defenestration, and inconsistent perisinusoidal extracellular matrix deposition. Aged hepatocytes were characterized by hypertrophy, cytoplasmic vacuolization and a significant increase in the volume densities of the nuclei, mitochondria and dense bodies. Lipofuscin accumulation and decreased microvilli in bile canaliculi and space of Disse also were observed. The adverse alterations were ameliorated significantly by both ginger and ALA supplementation; ALA was more effective than ginger. Ginger and ALA appear to be promising anti-aging agents based on their amelioration of ultrastructural alterations in livers of old rats.

Effects of Clozapine and Alprazolam on Cognitive Deficits and Anxiety-Like Behaviors in a Ketamine-Induced Rat Model of Schizophrenia

DTIC Science & Technology

2005-01-01

xii LIST OF TABLES Table 1. DSM-IV-TR Criteria for Schizophrenia (abbreviated) Table 2. Experimental Design Table 3. Experiment #1... Experimental Timeline Table 4. Experiment #2: Experimental Timeline Table 5. Experiment #1: Results of MANOVAs for Prepulse Inhibition Variables...rats. Please see Table 2 for a description of treatments and cell sizes for each experiment . Table 2. Experimental Design Ketamine (mg/kg

Extracts of Bauhinia championii (Benth.) Benth. inhibit NF-B-signaling in a rat model of collagen-induced arthritis and primary synovial cells.

PubMed

Xu, Wei; Huang, Mingqing; Zhang, Yuqin; Li, Huang; Zheng, Haiyin; Yu, Lishuang; Chu, Kedan

2016-06-05

Bauhinia championii (Benth.) Benth. is used in Chinese traditional medicine to treat arthritis, especially has been used a long time ago on rheumatoid arthritis (RA) in She ethnic minority group. To investigate the anti-RA effect of Bauhinia championii (Benth.) Benth ethyl acetate extract (BCBEE) and the molecular bases of it. BCBEE was studied on a rat model of RA induced by Ⅱcollagen in vivo, as well as on primary synovial cells in vitro. After BCBEE treatment, in vivo, it was showed that paw and joint edema was inhibited, pathological joint changes was ameliorated and the levels of interleukin (IL)-1β and tumor necrosis factor-(TNF-α) was decreased significantly. The protein and mRNA expressions of nuclear factor-B (NF-κB)(p65), IκB, p-IκB and IκB kinase beta (IκKβ) were also down-regulated. Moreover, the in vitro study revealed that BCBEE treatment inhibited primary synovial cells proliferation, and promoted down-regulation of NF-κB(p65), IκB, p-IκB and IκKβ. Taken together, the present study demonstrates that BCBEE produces a protection in a rat model of RA induced by Ⅱcollagen via inhibiting paw and joint edema, ameliorating pathological joint changes and regulating the levels of cytokines and its action mechanism maybe is via down-regulating NF-κB(p65), IκB, p-IκB and IκKβ expression. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

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.

Pregnancy amelioration of arthritis in SKG mice corresponds with alterations in serum amyloid A3 levels.

PubMed

Shaw, Laura A; Stefanski, Adrianne L; Peterson, Lisa K; Rumer, Kristen K; Vondracek, Andrea; Phang, Tzu L; Sakaguchi, Shimon; Winn, Virginia D; Dragone, Leonard L

2012-06-30

OBJECTIVES: Pregnancy leads to rheumatoid arthritis remission in humans. The objective of this study was to determine if the SKG mouse could serve as a model for pregnancy-associated inflammatory arthritis amelioration. In addition, the maternal peripheral blood mononuclear cell (PBMC) transcriptome was assessed to define a biomarker associated with remission. METHODS: Cohorts of zymosan-treated pregnant SKG mice and controls were monitored for arthritis progression. Microarray analysis evaluated alterations in gene expression in maternal PBMCs at embryonic day 14.5 (E14.5) between arthritic and pregnancy-remitted mice. A selected target, serum amyloid A3 (SAA3), was further investigated using quantitative reverse transcriptase PCR (qRT-PCR) and an enzyme-linked immunosorbent assay (ELISA). RESULTS: Pregnancy resulted in complete or partial remission in the majority of the zymosan-treated SKG mice. Twenty-seven transcripts were differentially expressed in the PBMCs between arthritic and pregnancy-remitted mice. Expression and plasma SAA3 levels decreased with pregnancy-induced arthritis amelioration and plasma SAA3 levels correlated with arthritis severity. CONCLUSIONS: These results establish the SKG mouse as a model system to study pregnancy-induced amelioration of arthritis. These studies also establish SAA3 as a biomarker of arthritis amelioration in SKG mice. This model can be used to elucidate the molecular and cellular mechanisms underlying the impact of pregnancy on the maternal immune system that results in arthritis amelioration.

Blocking pulmonary ICAM-1 expression ameliorates lung injury in established diet-induced pancreatitis.

PubMed

Lundberg, A H; Fukatsu, K; Gaber, L; Callicutt, S; Kotb, M; Wilcox, H; Kudsk, K; Gaber, A O

2001-02-01

To determine whether blocking the cell surface expression of intracellular adhesion molecules (ICAM-1) in established severe acute pancreatitis (AP) would ameliorate pulmonary injury. Lung injury in AP is in part mediated by infiltrating leukocytes, which are directed to lung tissue by ICAM-l. The authors' laboratory has previously demonstrated that AP results in overproduction of inflammatory cytokines, upregulation of pulmonary ICAM-1 expression, and a concomitant infiltration of neutrophils, which results in lung injury. Young female mice were fed a choline-deficient/ethionine-supplemented diet to induce AP and were treated with a blocking dose of monoclonal antibody specific to the ICAM-1 receptor. Antibody treatment was administered at 72, 96, and 120 hours after beginning the diet, and all animals were killed at 144 hours. The degree of pancreatitis was evaluated by serum biochemical and tumor necrosis factor alpha levels as well as histology. The dual radiolabeled monoclonal antibody method was used to quantitate ICAM-1 cell surface expression in pulmonary tissue. Lung injury was assessed histologically and by determining lung microvascular permeability by measuring accumulated 125I-radiolabeled albumin. Pulmonary neutrophil sequestration was determined by the myeloperoxidase assay. All mice developed severe AP, and pancreatic injury was equally severe in both treated and untreated groups. Pulmonary ICAM-1 expression was significantly upregulated in animals with AP compared with controls. Treatment with a blocking dose of anti-ICAM-1 antibody after the induction of AP resulted in inhibited ICAM-1 cell surface expression to near control levels. Compared to untreated animals with AP, mice treated with anti-ICAM-1 mice had significantly reduced histologic lung injury and neutrophil sequestration, and a decreased microvascular permeability by more than twofold. These results demonstrate for the first time that treatment targeting the cell surface expression of

Ensete superbum ameliorates renal dysfunction in experimental diabetes mellitus.

PubMed

Sreekutty, M S; Mini, S

2016-01-01

Hyperglycemia mediated oxidative stress plays a key role in the pathogenesis of diabetic complications like nephropathy. In the present study, we evaluated the effect of ethanolic extract of Ensete superbum seeds (ESSE) on renal dysfunction and oxidative stress in streptozotocin-induced diabetic rats. Glucose, HbA1c, total protein, albumin, renal function markers (urea, uric acid and creatinine), and lipid peroxidation levels were evaluated. Renal enzymatic and non-enzymatic antioxidants were examined along with renal histopathological study. ESSE (400 mg/kg BW t) administration reduced glucose and HbA1c, and improved serum total protein and albumin in diabetic rats. ESSE in diabetic rats recorded decrement in renal function markers and renal lipid peroxidation products along with significant increment in enzymatic and non-enzymatic antioxidants. Renal morphological abnormalities of diabetic rats were markedly ameliorated by E. superbum. These results suggest that the antioxidant effect of E. superbum could ameliorate oxidative stress and delay/prevent the progress of diabetic nephropathy in diabetes mellitus.

Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis.

PubMed

Di Paolo, Julie A; Huang, Tao; Balazs, Mercedesz; Barbosa, James; Barck, Kai H; Bravo, Brandon J; Carano, Richard A D; Darrow, James; Davies, Douglas R; DeForge, Laura E; Diehl, Lauri; Ferrando, Ronald; Gallion, Steven L; Giannetti, Anthony M; Gribling, Peter; Hurez, Vincent; Hymowitz, Sarah G; Jones, Randall; Kropf, Jeffrey E; Lee, Wyne P; Maciejewski, Patricia M; Mitchell, Scott A; Rong, Hong; Staker, Bart L; Whitney, J Andrew; Yeh, Sherry; Young, Wendy B; Yu, Christine; Zhang, Juan; Reif, Karin; Currie, Kevin S

2011-01-01

Bruton's tyrosine kinase (Btk) is a therapeutic target for rheumatoid arthritis, but the cellular and molecular mechanisms by which Btk mediates inflammation are poorly understood. Here we describe the discovery of CGI1746, a small-molecule Btk inhibitor chemotype with a new binding mode that stabilizes an inactive nonphosphorylated enzyme conformation. CGI1746 has exquisite selectivity for Btk and inhibits both auto- and transphosphorylation steps necessary for enzyme activation. Using CGI1746, we demonstrate that Btk regulates inflammatory arthritis by two distinct mechanisms. CGI1746 blocks B cell receptor-dependent B cell proliferation and in prophylactic regimens reduces autoantibody levels in collagen-induced arthritis. In macrophages, Btk inhibition abolishes FcγRIII-induced TNFα, IL-1β and IL-6 production. Accordingly, in myeloid- and FcγR-dependent autoantibody-induced arthritis, CGI1746 decreases cytokine levels within joints and ameliorates disease. These results provide new understanding of the function of Btk in both B cell- or myeloid cell-driven disease processes and provide a compelling rationale for targeting Btk in rheumatoid arthritis.

Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis

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

Di Paolo, Julie A; Huang, Tao; Balazs, Mercedesz

Bruton's tyrosine kinase (Btk) is a therapeutic target for rheumatoid arthritis, but the cellular and molecular mechanisms by which Btk mediates inflammation are poorly understood. Here we describe the discovery of CGI1746, a small-molecule Btk inhibitor chemotype with a new binding mode that stabilizes an inactive nonphosphorylated enzyme conformation. CGI1746 has exquisite selectivity for Btk and inhibits both auto- and transphosphorylation steps necessary for enzyme activation. Using CGI1746, we demonstrate that Btk regulates inflammatory arthritis by two distinct mechanisms. CGI1746 blocks B cell receptor–dependent B cell proliferation and in prophylactic regimens reduces autoantibody levels in collagen-induced arthritis. In macrophages, Btkmore » inhibition abolishes FcγRIII-induced TNFα, IL-1β and IL-6 production. Accordingly, in myeloid- and FcγR-dependent autoantibody-induced arthritis, CGI1746 decreases cytokine levels within joints and ameliorates disease. These results provide new understanding of the function of Btk in both B cell– or myeloid cell–driven disease processes and provide a compelling rationale for targeting Btk in rheumatoid arthritis.« less

Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis

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

Di Paolo, Julie A.; Huang, Tao; Balazs, Mercedesz

Bruton's tyrosine kinase (Btk) is a therapeutic target for rheumatoid arthritis, but the cellular and molecular mechanisms by which Btk mediates inflammation are poorly understood. Here we describe the discovery of CGI1746, a small-molecule Btk inhibitor chemotype with a new binding mode that stabilizes an inactive nonphosphorylated enzyme conformation. CGI1746 has exquisite selectivity for Btk and inhibits both auto- and transphosphorylation steps necessary for enzyme activation. Using CGI1746, we demonstrate that Btk regulates inflammatory arthritis by two distinct mechanisms. CGI1746 blocks B cell receptor-dependent B cell proliferation and in prophylactic regimens reduces autoantibody levels in collagen-induced arthritis. In macrophages, Btkmore » inhibition abolishes Fc{gamma}RIII-induced TNF{alpha}, IL-1{beta} and IL-6 production. Accordingly, in myeloid- and Fc{gamma}R-dependent autoantibody-induced arthritis, CGI1746 decreases cytokine levels within joints and ameliorates disease. These results provide new understanding of the function of Btk in both B cell- or myeloid cell-driven disease processes and provide a compelling rationale for targeting Btk in rheumatoid arthritis.« less

Kallistatin Ameliorates Influenza Virus Pathogenesis by Inhibition of Kallikrein-Related Peptidase 1-Mediated Cleavage of Viral Hemagglutinin

PubMed Central

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

2015-01-01

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

Local anesthetic lidocaine inhibits TRPM7 current and TRPM7-mediated zinc toxicity.

PubMed

Leng, Tian-Dong; Lin, Jun; Sun, Hua-Wei; Zeng, Zhao; O'Bryant, Zaven; Inoue, Koichi; Xiong, Zhi-Gang

2015-01-01

Previous study demonstrated that overstimulation of TRPM7 substantially contributes to zinc-mediated neuronal toxicity. Inhibition of TRPM7 activity and TRPM7-mediated intracellular Zn(2+) accumulation may represent a promising strategy in the treatment of stroke. To investigate whether local anesthetics lidocaine could inhibit TRPM7 channel and TRPM7-mediated zinc toxicity. Whole-cell patch-clamp technique was used to investigate the effect of local anesthetics on TRPM7 currents in cultured mouse cortical neurons and TRPM7-overexpressed HEK293 cells. Fluorescent Zn(2+) imaging technique was used to study the effect of lidocaine on TRPM7-mediated intracellular Zn(2+) accumulation. TRPM7-mediated zinc toxicity in neurons was used to evaluate the neuroprotective effect of lidocaine. (1) Lidocaine dose dependently inhibits TRPM7-like currents, with an IC50 of 11.55 and 11.06 mM in cultured mouse cortical neurons and TRPM7-overexpressed HEK293 cells, respectively; (2) Lidocaine inhibits TRPM7 currents in a use/frequency-dependent manner; (3) Lidocaine inhibits TRPM7-mediated intracellular Zn(2+) accumulation in both cortical neurons and TRPM7-overexpressed HEK293 cells; (4) TRPM7-mediated Zn(2+) toxicity is ameliorated by lidocaine in cortical neurons; (5) QX-314 has a similar inhibitory effect as lidocaine on TRPM7 currents when applied extracellularly; (6) Procaine also shows potent inhibitory effect on the TRPM7 currents in cortical neurons. Our data provide the first evidence that local anesthetic lidocaine inhibits TRPM7 channel and TRPM7-mediated zinc toxicity. © 2014 John Wiley & Sons Ltd.

Glucagon-like peptide-1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway.

PubMed

Wu, Lujin; Wang, Ke; Wang, Wei; Wen, Zheng; Wang, Peihua; Liu, Lei; Wang, Dao Wen

2018-04-16

Lipotoxicity cardiomyopathy is the result of excessive accumulation and oxidation of toxic lipids in the heart. It is a major threat to patients with diabetes. Glucagon-like peptide-1 (GLP-1) has aroused considerable interest as a novel therapeutic target for diabetes mellitus because it stimulates insulin secretion. Here, we investigated the effects and mechanisms of the GLP-1 analog exendin-4 and the dipeptidyl peptidase-4 inhibitor saxagliptin on cardiac lipid metabolism in diabetic mice (DM). The increased myocardial lipid accumulation, oxidative stress, apoptosis, and cardiac remodeling and dysfunction induced in DM by low streptozotocin doses and high-fat diets were significantly reversed by exendin-4 and saxagliptin treatments for 8 weeks. We found that exendin-4 inhibited abnormal activation of the (PPARα)-CD36 pathway by stimulating protein kinase A (PKA) but suppressing the Rho-associated protein kinase (ROCK) pathway in DM hearts, palmitic acid (PA)-treated rat h9c2 cardiomyocytes (CMs), and isolated adult mouse CMs. Cardioprotection in DM mediated by exendin-4 was abolished by combination therapy with the PPARα agonist wy-14643 but mimicked by PPARα gene deficiency. Therefore, the PPARα pathway accounted for the effects of exendin-4. This conclusion was confirmed in cardiac-restricted overexpression of PPARα mediated by adeno-associated virus serotype-9 containing a cardiac troponin T promoter. Our results provide the first direct evidence that GLP-1 protects cardiac function by inhibiting the ROCK/PPARα pathway, thereby ameliorating lipotoxicity in diabetic cardiomyopathy. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

DADS Analogues Ameliorated the Cognitive Impairments of Alzheimer-Like Rat Model Induced by Scopolamine.

PubMed

Manral, Apra; Meena, Poonam; Saini, Vikas; Siraj, Fouzia; Shalini, Shruti; Tiwari, Manisha

2016-10-01

The development of agents that affect two or more relevant targets has drawn considerable attention in treatment of AD. Diallyl disulfide (DADS), an active principle of garlic, has been reported to prevent APP processing by amyloidogenic pathway. Recently, we have reported a new series of DADS derivatives and our findings revealed that compound 7k and 7l could provide good templates for developing new multifunctional agents for AD treatment. Thus, the present study was constructed to investigate the neuroprotective effect of DADS analogues (7k and 7l) against Aβ-induced neurotoxicity in SH-SY5Y human neuroblastoma cells and in ameliorating the cognition deficit induced by scopolamine in rat model. The results indicated that compound 7k and 7l significantly inhibited Aβ1-42-induced neuronal cell death by inhibiting ROS generation. Moreover, they prevented apoptosis, in response to ROS, by restoring normal Bax/Bcl-2 ratio. Furthermore, it was observed that scopolamine-induced memory impairment was coupled by alterations in neurotransmitters, acetylcholinesterase activity and oxidative stress markers. Histological analysis revealed severe damaging effects of scopolamine on the structure of cerebral cortex and hippocampus. Administration of compounds 7k and 7l at 5 mg/kg significantly reversed scopolamine-induced behavioural, biochemical, neurochemical and histological changes in a manner comparable to standard donepezil. Together the present findings and previous studies indicate that compounds 7k and 7l have neuroprotective and cognition-enhancing effects, which makes them a promising multi-target candidate for addressing the complex nature of AD.

Chotosan, a kampo formula, ameliorates chronic cerebral hypoperfusion-induced deficits in object recognition behaviors and central cholinergic systems in mice.

PubMed

Zhao, Qi; Murakami, Yukihisa; Tohda, Michihisa; Obi, Ryosuke; Shimada, Yutaka; Matsumoto, Kinzo

2007-04-01

We previously demonstrated that the Kampo formula chotosan (CTS) ameliorated spatial cognitive impairment via central cholinergic systems in a chronic cerebral hypoperfusion (P2VO) mouse model. In this study, the object discrimination tasks were used to determine if the ameliorative effects of CTS on P2VO-induced cognitive deficits are a characteristic pharmacological profile of this formula, with the aim of clarifying the mechanisms by which CTS enhances central cholinergic function in P2VO mice. The cholinesterase inhibitor tacrine (THA) and Kampo formula saikokeishito (SKT) were used as controls. P2VO impaired object discrimination performance in the object recognition, location, and context tests. Daily administration of CTS (750 mg/kg, p.o.) and THA (2.5 mg/kg, i.p.) improved the object discrimination deficits, whereas SKT (750 mg/kg, p.o.) did not. In ex vivo assays, tacrine but not CTS or SKT inhibited cortical cholinesterase activity. P2VO reduced the mRNA expression of m(3) and m(5) muscarinic receptors and choline acetyltransferase but not that of other muscarinic receptor subtypes in the cerebral cortex. Daily administration of CTS and THA but not SKT reversed these expression changes. These results suggest that CTS and THA improve P2VO-induced cognitive impairment by normalizing the deficit of central cholinergic systems and that the beneficial effect on P2VO-induced cognitive deficits is a distinctive pharmacological characteristic of CTS.

Human umbilical cord-derived mesenchymal stem cells protect from hyperoxic lung injury by ameliorating aberrant elastin remodeling in the lung of O2-exposed newborn rat.

PubMed

Hou, Chen; Peng, Danyi; Gao, Li; Tian, Daiyin; Dai, Jihong; Luo, Zhengxiu; Liu, Enmei; Chen, Hong; Zou, Lin; Fu, Zhou

2018-01-08

The incidence and mortality rates of bronchopulmonary dysplasia (BPD) remain very high. Therefore, novel therapies are imminently needed to improve the outcome of this disease. Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) show promising therapeutic effects on oxygen-induced model of BPD. In our experiment, UC-MSCs were intratracheally delivered into the newborn rats exposed to hyperoxia, a well-established BPD model. This study demonstrated that UC-MSCs reduce elastin expression stimulated by 90% O 2 in human lung fibroblasts-a (HLF-a), and inhibit HLF-a transdifferentiation into myofibroblasts. In addition, the therapeutic effects of UC-MSCs in neonatal rats with BPD, UC-MSCs could inhibit lung elastase activity and reduce aberrant elastin expression and deposition in the lung of BPD rats. Overall, this study suggested that UC-MSCs could ameliorate aberrant elastin expression in the lung of hyperoxia-induced BPD model which may be associated with suppressing increased TGFβ1 activation. Copyright © 2017. Published by Elsevier Inc.

Formononetin Administration Ameliorates Dextran Sulfate Sodium-Induced Acute Colitis by Inhibiting NLRP3 Inflammasome Signaling Pathway.

PubMed

Wu, Dacheng; Wu, Keyan; Zhu, Qingtian; Xiao, Weiming; Shan, Qing; Yan, Zhigang; Wu, Jian; Deng, Bin; Xue, Yan; Gong, Weijuan; Lu, Guotao; Ding, Yanbing

2018-01-01

Formononetin is a kind of isoflavone compound and has been reported to possess anti-inflammatory properties. In this present study, we aimed to explore the protective effects of formononetin on dextran sulfate sodium- (DSS-) induced acute colitis. By intraperitoneal injection of formononetin in mice, the disease severity of colitis was attenuated in a dose-dependent manner, mainly manifesting as relieved clinical symptoms of colitis, mitigated colonic epithelial cell injury, and upregulations of colonic tight junction proteins levels (ZO-1, claudin-1, and occludin). Meanwhile, our study found that formononetin significantly prevented acute injury of colonic cells induced by TNF- α in vitro, specifically manifesting as the increased expressions of colonic tight junction proteins (ZO-1, claudin-1, and occludin). In addition, the result showed that formononetin could reduce the NLRP3 pathway protein levels (NLRP3, ASC, IL-1 β ) in vivo and vitro, and MCC950, the NLRP3 specific inhibitor, could alleviate the DSS-induced mice acute colitis. Furthermore, in the foundation of administrating MCC950 to inhibit activation of NLRP3 inflammasome, we failed to observe the protective effects of formononetin on acute colitis in mice. Collectively, our study for the first time confirmed the protective effects of formononetin on DSS-induced acute colitis via inhibiting the NLRP3 inflammasome pathway activation.

Selective deletion of apolipoprotein E in astrocytes ameliorates the spatial learning and memory deficits in Alzheimer's disease (APP/PS1) mice by inhibiting TGF-β/Smad2/STAT3 signaling.

PubMed

Zheng, Jin-Yu; Sun, Jian; Ji, Chun-Mei; Shen, Lin; Chen, Zhong-Jun; Xie, Peng; Sun, Yuan-Zhao; Yu, Ru-Tong

2017-06-01

Astrocytes and apolipoprotein E (apoE) play critical roles in cognitive function, not only under physiological conditions but also in some pathological situations, particularly in the pathological progression of Alzheimer's disease (AD). The regulatory mechanisms underlying the effect of apoE, derived from astrocytes, on cognitive deficits during AD pathology development are unclear. In this study, we generated amyloid precursor protein/apoE knockout (APP/apoE KO ) and APP/glial fibrillary acidic protein (GFAP)-apoE KO mice (the AD mice model used in this study was based on the APP-familial Alzheimer disease overexpression) to investigate the role of apoE, derived from astrocytes, in AD pathology and cognitive function. To explore the mechanism, we investigated the amyloidogenic process related transforming growth factor β/mothers against decapentaplegic homolog 2/signal transducer and activator of transcription 3 (TGF-β/Smad2/STAT3) signaling pathway and further confirmed by administering TGF-β-overexpression adeno-associated virus (specific to astrocytes) to APP/GFAP-apoE KO mice and TGF-β-inhibition adeno-associated virus (specific to astrocytes) to APP/WT mice. Whole body deletion of apoE significantly ameliorated the spatial learning and memory impairment, reduced amyloid β-protein production and inhibited astrogliosis in APP/apoE KO mice, as well as specific deletion apoE in astrocytes in APP/GFAP-apoE KO mice. Moreover, amyloid β-protein accumulation was increased due to promotion of amyloidogenesis of APP, and astrogliosis was upregulated by activation of TGF-β/Smad2/STAT3 signaling. Furthermore, the overexpression of TGF-β in astrocytes in APP/GFAP-apoE KO mice abrogated the effects of apoE knockout. In contrast, repression of TGF-β in astrocytes of APP/WT mice exerted a therapeutic effect similar to apoE knockout. These data suggested that apoE derived from astrocytes contributes to the risk of AD through TGF-β/Smad2/STAT3 signaling activation

Baclofen, a GABABR Agonist, Ameliorates Immune-Complex Mediated Acute Lung Injury by Modulating Pro-Inflammatory Mediators

PubMed Central

Jin, Shunying; Merchant, Michael L.; Ritzenthaler, Jeffrey D.; McLeish, Kenneth R.; Lederer, Eleanor D.; Torres-Gonzalez, Edilson; Fraig, Mostafa; Barati, Michelle T.; Lentsch, Alex B.; Roman, Jesse; Klein, Jon B.; Rane, Madhavi J.

2015-01-01

Immune-complexes play an important role in the inflammatory diseases of the lung. Neutrophil activation mediates immune-complex (IC) deposition-induced acute lung injury (ALI). Components of gamma amino butyric acid (GABA) signaling, including GABA B receptor 2 (GABABR2), GAD65/67 and the GABA transporter, are present in the lungs and in the neutrophils. However, the role of pulmonary GABABR activation in the context of neutrophil-mediated ALI has not been determined. Thus, the objective of the current study was to determine whether administration of a GABABR agonist, baclofen would ameliorate or exacerbate ALI. We hypothesized that baclofen would regulate IC-induced ALI by preserving pulmonary GABABR expression. Rats were subjected to sham injury or IC-induced ALI and two hours later rats were treated intratracheally with saline or 1 mg/kg baclofen for 2 additional hours and sacrificed. ALI was assessed by vascular leakage, histology, TUNEL, and lung caspase-3 cleavage. ALI increased total protein, tumor necrosis factor α (TNF-α and interleukin-1 receptor associated protein (IL-1R AcP), in the bronchoalveolar lavage fluid (BALF). Moreover, ALI decreased lung GABABR2 expression, increased phospho-p38 MAPK, promoted IκB degradation and increased neutrophil influx in the lung. Administration of baclofen, after initiation of ALI, restored GABABR expression, which was inhibited in the presence of a GABABR antagonist, CGP52432. Baclofen administration activated pulmonary phospho-ERK and inhibited p38 MAPK phosphorylation and IκB degradation. Additionally, baclofen significantly inhibited pro-inflammatory TNF-α and IL-1βAcP release and promoted BAL neutrophil apoptosis. Protective effects of baclofen treatment on ALI were possibly mediated by inhibition of TNF-α- and IL-1β-mediated inflammatory signaling. Interestingly, GABABR2 expression was regulated in the type II pneumocytes in lung tissue sections from lung injured patients, further suggesting a

Apigenin and naringenin regulate glucose and lipid metabolism, and ameliorate vascular dysfunction in type 2 diabetic rats.

PubMed

Ren, Bei; Qin, Weiwei; Wu, Feihua; Wang, Shanshan; Pan, Cheng; Wang, Liying; Zeng, Biao; Ma, Shiping; Liang, Jingyu

2016-02-15

Vascular endothelial dysfunction is regarded as the initial step of vascular complications in diabetes mellitus. This study investigated the amelioration of apigenin and naringenin in type 2 diabetic (T2D) rats induced by high-fat diet and streptozotocin and explored the underlying mechanism. Apigenin or naringenin was intragastrically administered at 50 or 100mg/kg once a day for 6 weeks. Biochemical parameters including blood glucose, glycated serum protein, serum lipid, insulin, superoxide dismutase (SOD), malonaldehyde and intercellular adhesion molecule-1 (ICAM-1) were measured. Vascular reactivity in isolated thoracic aortic rings was examined. Pathological features of the thoracic aorta were further observed through optical microscopy and transmission electron microscopy. Lastly, we evaluated their effects on insulin resistance of palmitic acid (PA)-induced endothelial cells. Compared with diabetic control group, apigenin and naringenin significantly decreased the levels of blood glucose, serum lipid, malonaldehyde, ICAM-1 and insulin resistance index, increased SOD activity and improved impaired glucose tolerance. Apigenin and naringenin restored phenylephrine-mediated contractions and acetylcholine or insulin-induced relaxations in aortic tissues. Furthermore, pathological damage in the thoracic aorta of apigenin and naringenin groups was more remissive than diabetic control group. In vitro, apigenin and naringenin inhibited NF-κB activation and ICAM-1 mRNA expression in PA-treated endothelial cells and improved nitric oxide production in the presence of insulin. In conclusion, both apigenin and naringenin can ameliorate glucose and lipid metabolism, as well as endothelial dysfunction in T2D rats at least in part by down-regulating oxidative stress and inflammation. In general, apigenin showed greater potency than naringenin equivalent. Copyright © 2016 Elsevier B.V. All rights reserved.

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

PubMed

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

2016-07-20

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

Pregnancy amelioration of arthritis in SKG mice corresponds with alterations in serum amyloid A3 levels

PubMed Central

Shaw, Laura A; Stefanski, Adrianne L; Peterson, Lisa K; Rumer, Kristen K; Vondracek, Andrea; Phang, Tzu L; Sakaguchi, Shimon; Winn, Virginia D; Dragone, Leonard L

2012-01-01

Objectives: Pregnancy leads to rheumatoid arthritis remission in humans. The objective of this study was to determine if the SKG mouse could serve as a model for pregnancy-associated inflammatory arthritis amelioration. In addition, the maternal peripheral blood mononuclear cell (PBMC) transcriptome was assessed to define a biomarker associated with remission. Methods: Cohorts of zymosan-treated pregnant SKG mice and controls were monitored for arthritis progression. Microarray analysis evaluated alterations in gene expression in maternal PBMCs at embryonic day 14.5 (E14.5) between arthritic and pregnancy-remitted mice. A selected target, serum amyloid A3 (SAA3), was further investigated using quantitative reverse transcriptase PCR (qRT-PCR) and an enzyme-linked immunosorbent assay (ELISA). Results: Pregnancy resulted in complete or partial remission in the majority of the zymosan-treated SKG mice. Twenty-seven transcripts were differentially expressed in the PBMCs between arthritic and pregnancy-remitted mice. Expression and plasma SAA3 levels decreased with pregnancy-induced arthritis amelioration and plasma SAA3 levels correlated with arthritis severity. Conclusions: These results establish the SKG mouse as a model system to study pregnancy-induced amelioration of arthritis. These studies also establish SAA3 as a biomarker of arthritis amelioration in SKG mice. This model can be used to elucidate the molecular and cellular mechanisms underlying the impact of pregnancy on the maternal immune system that results in arthritis amelioration. PMID:23097751

MHY1485 ameliorates UV-induced skin cell damages via activating mTOR-Nrf2 signaling.

PubMed

Yang, Bo; Xu, Qiu-Yun; Guo, Chun-Yan; Huang, Jin-Wen; Wang, Shu-Mei; Li, Yong-Mei; Tu, Ying; He, Li; Bi, Zhi-Gang; Ji, Chao; Cheng, Bo

2017-02-21

Ultra Violet (UV)-caused skin cell damage is a main cause of skin cancer. Here, we studied the activity of MHY1485, a mTOR activator, in UV-treated skin cells. In primary human skin keratinocytes, HaCaT keratinocytes and human skin fibroblasts, MHY1485 ameliorated UV-induced cell death and apoptosis. mTOR activation is required for MHY1485-induced above cytoprotective actions. mTOR kinase inhibitors (OSI-027, AZD-8055 and AZD-2014) or mTOR shRNA knockdown almost abolished MHY1485-induced cytoprotection. Further, MHY1485 treatment in skin cells activated mTOR downstream NF-E2-related factor 2 (Nrf2) signaling, causing Nrf2 Ser-40 phosphorylation, stabilization/upregulation and nuclear translocation, as well as mRNA expression of Nrf2-dictated genes. Contrarily, Nrf2 knockdown or S40T mutation almost nullified MHY1485-induced cytoprotection. MHY1485 suppressed UV-induced reactive oxygen species production and DNA single strand breaks in skin keratinocytes and fibroblasts. Together, we conclude that MHY1485 inhibits UV-induced skin cell damages via activating mTOR-Nrf2 signaling.

The indole compound NC009-1 inhibits aggregation and promotes neurite outgrowth through enhancement of HSPB1 in SCA17 cells and ameliorates the behavioral deficits in SCA17 mice.

PubMed

Chen, Chiung-Mei; Chen, Wan-Ling; Hung, Chen-Ting; Lin, Te-Hsien; Chao, Chih-Ying; Lin, Chih-Hsin; Wu, Yih-Ru; Chang, Kuo-Hsuan; Yao, Ching-Fa; Lee-Chen, Guey-Jen; Su, Ming-Tsan; Hsieh-Li, Hsiu Mei

2018-06-21

Spinocerebellar ataxia type 17 (SCA17) is caused by the expansion of translated CAG repeat in the TATA box binding protein (TBP) gene encoding a long polyglutamine (polyQ) tract in the TBP protein, which leads to intracellular accumulation of aggregated TBP and cell death. The molecular chaperones act in preventing protein aggregation to ameliorate downstream harmful events. In this study, we used Tet-On cells with inducible SCA17 TBP/Q 79 -GFP expression to test five in-house NC009 indole compounds for neuroprotection. We found that both aggregation and polyQ-induced reactive oxygen species can be significantly prohibited by the tested NC009 compounds in Tet-On TBP/Q 79 293 cells. Among the five indole compounds, NC009-1 up-regulated expression of heat shock protein family B (small) member 1 (HSPB1) chaperone to reduce polyQ aggregation and promote neurite outgrowth in neuronal differentiated TBP/Q 79 SH-SY5Y cells. The increased HSPB1 thus ameliorated the increased BH3 interacting domain death agonist (BID), cytochrome c (CYCS) release, and caspase 3 (CASP3) activation which result in apoptosis. Knock down of HSPB1 attenuated the effects of NC009-1 on TBP/Q 79 SH-SY5Y cells, suggesting that HSPB1 might be one of the major pathways involved for NC009-1 effects. NC009-1 further reduced polyQ aggregation in Purkinje cells and ameliorated behavioral deficits in SCA17 TBP/Q 109 transgenic mice. Our results suggest that NC009-1 has a neuroprotective effect on SCA17 cell and mouse models to support its therapeutic potential in SCA17 treatment. Copyright © 2018 Elsevier B.V. All rights reserved.

Ameliorative effect of pumpkin seed oil against emamectin induced toxicity in mice.

PubMed

Abou-Zeid, Shimaa M; AbuBakr, Huda O; Mohamed, Mostafa A; El-Bahrawy, Amanallah

2018-02-01

The current study was conducted to evaluate the toxic effects of emamectin insecticide in mice and the possible protective effect of pumpkin seed oil. Treated mice received emamectin benzoate in the diet at 75-ppm for 8 weeks, while another group of animals received emamectin in addition to pumpkin seed oil at a dose of 4 ml/kg. Biochemical analysis of MDA, DNA fragmentation, GSH, CAT and SOD was performed in liver, kidney and brain as oxidant/antioxidant biomarkers. In addition, gene expression of CYP2E1 and Mgst1 and histopathological alterations in these organs were evaluated. Emamectin administration induced oxidative stress in liver and kidney evidenced by elevated levels of MDA and percentage of DNA fragmentation with suppression of GSH level and CAT and SOD activities. Brain showed increase of MDA level with inhibition of SOD activity. Relative expressions of CYP2E1 and Mgst1 genes were significantly elevated in both liver and kidney. Emamectin produced several histopathological changes in liver, kidney and brain. Co-administration of pumpkin seed oil produced considerable protection of liver and kidney and complete protection of brain. In conclusion, pumpkin seed oil has valuable value in ameliorating the toxic insult produced by emamectin in mice. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

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

DTIC Science & Technology

2011-04-01

increase PPI, but dopamine agonists can have the opposite effect by reducing PPI. Fortunately, caffeine appears to have no significant effect on PPI...violent behavior, and sexual risk behavior. Landis, C., & Hunt, W.A. (1939). The Startle Pattern. New York: Farrar. An example of early research on

MiR-125a TNF receptor-associated factor 6 to inhibit osteoclastogenesis

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

Guo, Li-Juan; Liao, Lan; Yang, Li

MicroRNAs (miRNAs) play important roles in osteoclastogenesis and bone resorption. In the present study, we found that miR-125a was dramatically down-regulated during macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) induced osteoclastogenesis of circulating CD14+ peripheral blood mononuclear cells (PBMCs). Overexpression of miR-125a in CD14+ PBMCs inhibited osteoclastogenesis, while inhibition of miR-125a promoted osteoclastogenesis. TNF receptor-associated factor 6 (TRAF6), a transduction factor for RANKL/RANK/NFATc1 signal, was confirmed to be a target of miR-125a. EMSA and ChIP assays confirmed that NFATc1 bound to the promoter of the miR-125a. Overexpression of NFATc1 inhibited miR-125a transcription, and blockmore » of NFATc1 expression attenuated RANKL-regulated miR-125a transcription. Here, we reported that miR-125a played a biological function in osteoclastogenesis through a novel TRAF6/ NFATc1/miR-125a regulatory feedback loop. It suggests that regulation of miR-125a expression may be a potential strategy for ameliorating metabolic disease. - Highlights: • MiR-125a was significantly down-regulated in osteoclastogenesis of CD14+ PBMCs. • MiR-125a inhibited osteoclast differentiation by targeting TRAF6. • NFATc1 inhibited miR-125a transciption by binding to the promoter of miR-125a. • TRAF6/NFATc1 and miR-125a form a regulatory feedback loop in osteoclastogenesis.« less

6-Shogaol ameliorates diabetic nephropathy through anti-inflammatory, hyperlipidemic, anti-oxidative activity in db/db mice.

PubMed

Xu, Yun; Bai, Liwei; Chen, Xuehui; Li, Yan; Qin, Yan; Meng, Xiangyu; Zhang, Qinggui

2018-01-01

The prevalence of type 2 diabetes mellitus has been increasing worldwide and more than two thirds of the patients may develop diabetic nephropathy (DN). However, the efficiency of existing approaches on DN progression is limited. 6-Shogaol (6-SG), a major dehydrated derivative of gingerols, possesses various biological properties. The present study was designed to evaluate the possible effects of 6-SG on DN in db/db mice and to investigate the mechanisms. We revealed that 6-SG reduced the levels of fasting blood glucose, serum insulin, C-peptide, glycosylated hemoglobin A1c, and systolic blood pressure. 6-SG decreased the levels of blood urea nitrogen (BUN), serum creatinine, urinary albumin content and albumin/creatinine ratio (ACR), ameliorated the pathological injuries of kidneys, reduced the surface area of Bowman's capsule, Bowman's space, glomerular tuft, and decreased the expression of collagen IV and fibronectin in kidneys of db/db mice. The high levels of systemic and renal triglyceride and cholesterol were decreased by 6-SG. Moreover, 6-SG exhibited anti-inflammatory effects, as reflected by reduction of tumor necrosis factor ɑ (TNFɑ), monocyte chemotactic protein-1 (MCP-1), and IL-6 levels in circulation and kidneys, and decrease of NF-κB expression. Furthermore, 6-SG also inhibited oxidative stress and restored the expression of NF-E2-related factor 2 (Nrf2) in kidneys of db/db mice. In conclusion, we have demonstrated that 6-SG exhibits anti-diabetic and renal protective effects against DN, in which effect the anti-inflammatory, hyperlipidemic, anti-oxidative activities may be involved. Overall, 6-SG could be a promising therapeutic treatment to ameliorate diabetes and the development of DN. Copyright © 2017. Published by Elsevier Masson SAS.

1996 Toxic Hazards Research Annual Report.

DTIC Science & Technology

1998-01-01

gasoline , diesel fuel, and jet propulsion (JP) fuel (Staats, 1994). Millions of dollars are spent each year at petroleum contaminated sites for remediation...of locomotor activity and auditory startle reflex tests will be provided in the detailed technical report (in progress). Body Weights and Food...Olfactory Sensitization, Acoustic Startle, Prepulse Inhibition and Habituation, Total Locomotor Activity, Tail Flick Analgesia, and the Treadmill Test of

Low-Dose Paclitaxel Ameliorates Pulmonary Fibrosis by Suppressing TGF-β1/Smad3 Pathway via miR-140 Upregulation

PubMed Central

Wang, Congjie; Song, Xiaodong; Li, Youjie; Han, Fang; Gao, Shuyan; Wang, Xiaozhi; Xie, Shuyang; Lv, Changjun

2013-01-01

Abnormal TGF-β1/Smad3 activation plays an important role in the pathogenesis of pulmonary fibrosis, which can be prevented by paclitaxel (PTX). This study aimed to investigate an antifibrotic effect of the low-dose PTX (10 to 50 nM in vitro, and 0.6 mg/kg in vivo). PTX treatment resulted in phenotype reversion of epithelial-mesenchymal transition (EMT) in alveolar epithelial cells (AECs) with increase of miR-140. PTX resulted in an amelioration of bleomycin (BLM)-induced pulmonary fibrosis in rats with reduction of the wet lung weight to body weight ratios and the collagen deposition. Our results further demonstrated that PTX inhibited the effect of TGF-β1 on regulating the expression of Smad3 and phosphorylated Smad3 (p-Smad3), and restored the levels of E-cadherin, vimentin and α-SMA. Moreover, lower miR-140 levels were found in idiopathic pulmonary fibrosis (IPF) patients, TGF-β1-treated AECs and BLM-instilled rat lungs. Through decreasing Smad3/p-Smad3 expression and upregulating miR-140, PTX treatment could significantly reverse the EMT of AECs and prevent pulmonary fibrosis of rats. The action of PTX to ameliorate TGF-β1-induced EMT was promoted by miR-140, which increased E-cadherin levels and reduced the expression of vimentin, Smad3 and p-Smad3. Collectively, our results demonstrate that low-dose PTX prevents pulmonary fibrosis by suppressing the TGF-β1/Smad3 pathway via upregulating miR-140. PMID:23967091

Enhanced Production of Adenosine Triphosphate by Pharmacological Activation of Adenosine Monophosphate-Activated Protein Kinase Ameliorates Acetaminophen-Induced Liver Injury

PubMed Central

Hwang, Jung Hwan; Kim, Yong-Hoon; Noh, Jung-Ran; Choi, Dong-Hee; Kim, Kyoung-Shim; Lee, Chul-Ho

2015-01-01

The hepatic cell death induced by acetaminophen (APAP) is closely related to cellular adenosine triphosphate (ATP) depletion, which is mainly caused by mitochondrial dysfunction. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key sensor of low energy status. AMPK regulates metabolic homeostasis by stimulating catabolic metabolism and suppressing anabolic pathways to increase cellular energy levels. We found that the decrease in active phosphorylation of AMPK in response to APAP correlates with decreased ATP levels, in vivo. Therefore, we hypothesized that the enhanced production of ATP via AMPK stimulation can lead to amelioration of APAP-induced liver failure. A769662, an allosteric activator of AMPK, produced a strong synergistic effect on AMPK Thr172 phosphorylation with APAP in primary hepatocytes and liver tissue. Interestingly, activation of AMPK by A769662 ameliorated the APAP-induced hepatotoxicity in C57BL/6N mice treated with APAP at a dose of 400 mg/kg intraperitoneally. However, mice treated with APAP alone developed massive centrilobular necrosis, and APAP increased their serum alanine aminotransferase and aspartate aminotransferase levels. Furthermore, A769662 administration prevented the loss of intracellular ATP without interfering with the APAP-mediated reduction of mitochondrial dysfunction. In contrast, inhibition of glycolysis by 2-deoxy-glucose eliminated the beneficial effects of A769662 on APAP-mediated liver injury. In conclusion, A769662 can effectively protect mice against APAP-induced liver injury through ATP synthesis by anaerobic glycolysis. Furthermore, stimulation of AMPK may have potential therapeutic application for APAP overdose. PMID:26434492

Myeloid-Derived Suppressor Cells Ameliorate Cyclosporine A-Induced Hypertension in Mice.

PubMed

Chiasson, Valorie L; Bounds, Kelsey R; Chatterjee, Piyali; Manandhar, Lochana; Pakanati, Abhinandan R; Hernandez, Marcos; Aziz, Bilal; Mitchell, Brett M

2018-01-01

The calcineurin inhibitor cyclosporine A (CsA) suppresses the immune system but promotes hypertension, vascular dysfunction, and renal damage. CsA decreases regulatory T cells and this contributes to the development of hypertension. However, CsA's effects on another important regulatory immune cell subset, myeloid-derived suppressor cells (MDSCs), is unknown. We hypothesized that augmenting MDSCs would ameliorate the CsA-induced hypertension and vascular and renal injury and dysfunction and that CsA reduces MDSCs in mice. Daily interleukin-33 treatment, which increased MDSC levels, completely prevented CsA-induced hypertension and vascular and renal toxicity. Adoptive transfer of MDSCs from control mice into CsA-treated mice after hypertension was established dose-dependently reduced blood pressure and vascular and glomerular injury. CsA treatment of aortas and kidneys isolated from control mice for 24 hours decreased relaxation responses and increased inflammation, respectively, and these effects were prevented by the presence of MDSCs. MDSCs also prevented the CsA-induced increase in fibronectin in microvascular and glomerular endothelial cells. Last, CsA dose-dependently reduced the number of MDSCs by inhibiting calcineurin and preventing cell proliferation, as other direct calcineurin signaling pathway inhibitors had the same dose-dependent effect. These data suggest that augmenting MDSCs can reduce the cardiovascular and renal toxicity and hypertension caused by CsA. © 2017 American Heart Association, Inc.

Interleukin-37 ameliorates myocardial ischaemia/reperfusion injury in mice

PubMed Central

Wu, B; Meng, K; Ji, Q; Cheng, M; Yu, K; Zhao, X; Tony, H; Liu, Y; Zhou, Y; Chang, C; Zhong, Y; Zhu, Z; Zhang, W; Mao, X; Zeng, Q

2014-01-01

Innate immune and inflammatory responses are involved in myocardial ischaemia/reperfusion (I/R) injury. Interleukin (IL)-37 is a newly identified member of the IL-1 family, and functions as a fundamental inhibitor of innate immunity and inflammation. However, its role in myocardial I/R injury remains unknown. I/R or sham operations were performed on male C57BL/6J mice. I/R mice received an injection of recombinant human IL-37 or vehicle, immediately before reperfusion. Compared with vehicle treatment, mice treated with IL-37 showed an obvious amelioration of the I/R injury, as demonstrated by reduced infarct size, decreased cardiac troponin T level and improved cardiac function. This protective effect was associated with the ability of IL-37 to suppress production of proinflammatory cytokines, chemokines and neutrophil infiltration, which together contributed to a decrease in cardiomyocyte apoptosis and reactive oxygen species (ROS) generation. In addition, we found that IL-37 inhibited the up-regulation of Toll-like receptor (TLR)-4 expression and nuclear factor kappa B (NF-kB) activation after I/R, while increasing the anti-inflammatory IL-10 level. Moreover, the administration of anti-IL-10R antibody abolished the protective effects of IL-37 in I/R injury. In-vitro experiments further demonstrated that IL-37 protected cardiomyocytes from apoptosis under I/R condition, and suppressed the migration ability of neutrophils towards the chemokine LIX. In conclusion, IL-37 plays a protective role against mouse myocardial I/R injury, offering a promising therapeutic medium for myocardial I/R injury. PMID:24527881

Formononetin Administration Ameliorates Dextran Sulfate Sodium-Induced Acute Colitis by Inhibiting NLRP3 Inflammasome Signaling Pathway

PubMed Central

Wu, Dacheng; Wu, Keyan; Zhu, Qingtian; Xiao, Weiming; Shan, Qing; Yan, Zhigang; Wu, Jian; Deng, Bin; Xue, Yan; Gong, Weijuan

2018-01-01

Formononetin is a kind of isoflavone compound and has been reported to possess anti-inflammatory properties. In this present study, we aimed to explore the protective effects of formononetin on dextran sulfate sodium- (DSS-) induced acute colitis. By intraperitoneal injection of formononetin in mice, the disease severity of colitis was attenuated in a dose-dependent manner, mainly manifesting as relieved clinical symptoms of colitis, mitigated colonic epithelial cell injury, and upregulations of colonic tight junction proteins levels (ZO-1, claudin-1, and occludin). Meanwhile, our study found that formononetin significantly prevented acute injury of colonic cells induced by TNF-α in vitro, specifically manifesting as the increased expressions of colonic tight junction proteins (ZO-1, claudin-1, and occludin). In addition, the result showed that formononetin could reduce the NLRP3 pathway protein levels (NLRP3, ASC, IL-1β) in vivo and vitro, and MCC950, the NLRP3 specific inhibitor, could alleviate the DSS-induced mice acute colitis. Furthermore, in the foundation of administrating MCC950 to inhibit activation of NLRP3 inflammasome, we failed to observe the protective effects of formononetin on acute colitis in mice. Collectively, our study for the first time confirmed the protective effects of formononetin on DSS-induced acute colitis via inhibiting the NLRP3 inflammasome pathway activation. PMID:29507526

Sodium Meta-Arsenite Ameliorates Hyperglycemia in Obese Diabetic db/db Mice by Inhibition of Hepatic Gluconeogenesis

PubMed Central

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

2014-01-01

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

Reversal of social deficits by subchronic oxytocin in two autism mouse models

PubMed Central

Teng, Brian L.; Nikolova, Viktoriya D.; Riddick, Natallia V.; Agster, Kara L.; Crowley, James J.; Baker, Lorinda K.; Koller, Beverly H.; Pedersen, Cort A.; Jarstfer, Michael B.; Moy, Sheryl S.

2016-01-01

Social deficits are a hallmark feature of autism spectrum disorder (ASD) and related developmental syndromes. Although there is no standard treatment for social dysfunction, clinical studies have identified oxytocin as a potential therapeutic with prosocial efficacy. We have previously reported that peripheral oxytocin treatment can increase sociability and ameliorate repetitive stereotypy in adolescent mice from the C58/J model of ASD-like behavior. In the present study, we determined that prosocial oxytocin effects were not limited to the adolescent period, since C58/J mice, tested in adulthood, demonstrated significant social preference up to 2 weeks following subchronic oxytocin treatment. Oxytocin was also evaluated in adult mice with underexpression of the N-methyl-D-aspartate receptor NR1 subunit (encoded by Grin1), a genetic model of autism- and schizophrenia- like behavior. Subchronic oxytocin had striking prosocial efficacy in male Grin1 knockdown mice; in contrast, chronic regimens with clozapine (66 mg/kg/day) or risperidone (2 mg/kg/day) failed to reverse deficits in sociability. Neither the subchronic oxytocin regimen, nor chronic treatment with clozapine or risperidone, reversed impaired prepulse inhibition in the Grin1 knockdown mice. Overall, these studies demonstrate oxytocin can enhance sociability in mouse models with divergent genotypes and behavioral profiles, adding to the evidence that this neurohormone could have therapeutic prosocial efficacy across a spectrum of developmental disorders. PMID:26748053

RIP1 Inhibition Rescues from LPS-Induced RIP3-Mediated Programmed Cell Death, Distributed Energy Metabolism and Spatial Memory Impairment.

PubMed

Nikseresht, Sara; Khodagholi, Fariba; Nategh, Mohsen; Dargahi, Leila

2015-10-01

Receptor interacting protein 1 (RIP1) has a critical role in initiation of programmed necrosis or necroptosis. RIP1 in a close collaboration with RIP3 not only mediates necroptosis but also is involved in apoptosis and inflammatory signaling. However, the interpretation of the distinct function of RIP1 and RIP3 is complicated. Herein, we demonstrated that RIP1 inhibition in the context of LPS-induced neuroinflammation decreases RIP3 expression. Concomitant administration of Nec-1, specific inhibitor of RIP1, with LPS also attenuated the activating effect of RIP3 on metabolic enzymes, glutamate-ammonia ligase and glutamate dehydrogenase as bioenergetic determinants, in hippocampal and cortical cells. RIP1 inhibition possessed an anti-inflammatory effect and improved the antioxidant capacity against LPS. Interestingly, and opposed to some reports that necroptosis inhibition sensitizes cells to apoptosis, our results showed that RIP1 inhibition attenuates apoptotic cell death in response to LPS. The survival of neuronal function was also confirmed by measuring spontaneous alternations of rats in Y-maze. In conclusion, effects of RIP1 inhibition on RIP3 and cell death provide new approaches to ameliorate neuroinflammation and relative disorders.

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

PubMed

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

2016-10-01

Psoriasis is a chronic auto-immune inflammation disease with skin lesions and abnormal keratinocyte proliferation. The IL-23/IL-17 axis plays an important role in the pathogenesis of psoriasis. Madecassoside (MAD) was the most important constituents isolated from Centella asiatica, which has long been used in dermatology, and it is supposed that MAD may have effects on psoriasis. In the present study, the BALB/c mice ear and back skin received IMQ for 6 consecutive days to induce psoriasis-like dermatitis. MAD ointment was applied 6h later after IMQ treatment, and the IL-23/IL-17 pathway was investigated. The HE staining, BrdU and Psoriasis Area and Severity Index (PASI) were used to score the severity of keratinocyte proliferation and inflammation of the skin. Real-time PCR and Western Blot were used to detect the IL-23/IL-17 related cytokines. Flow Cytometry were applied to observe the numbers of Th17 cells. Daily application of IMQ for 6days on mouse ear skin and back skin induced psoriasis-like dermatitis. Real-time PCR showed that mRNA level of IL-23, IL-22, IL-17A were significantly decreased by MAD ointment treatment in ear skin. HE staining and BrdU incorporation implied that MAD ointment reduced keratinocyte proliferation. Flow Cytometry results showed MAD ointment decreased the numbers of Th17 cells. Thus, MAD ointment ameliorates Imiquimod-induced skin inflammation and abnormal keratinocyte through regulate the IL-23/IL-17 axis. Copyright © 2016 Elsevier B.V. All rights reserved.

Fenofibrate inhibits aldosterone-induced apoptosis in adult rat ventricular myocytes via stress-activated kinase-dependent mechanisms

PubMed Central

De Silva, Deepa S.; Wilson, Richard M.; Hutchinson, Christoph; Ip, Peter C.; Garcia, Anthony G.; Lancel, Steve; Ito, Masa; Pimentel, David R.; Sam, Flora

2009-01-01

Aldosterone induces extracellular signal-regulated kinase (ERK)-dependent cardiac remodeling. Fenofibrate improves cardiac remodeling in adult rat ventricular myocytes (ARVM) partly via inhibition of aldosterone-induced ERK1/2 phosphorylation and inhibition of matrix metalloproteinases. We sought to determine whether aldosterone caused apoptosis in cultured ARVM and whether fenofibrate ameliorated the apoptosis. Aldosterone (1 μM) induced apoptosis by increasing terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive nuclei in ARVM. Spironolactone (100 nM), an aldosterone receptor antagonist, but not RU-486, a glucocorticoid receptor, inhibited aldosterone-mediated apoptosis, indicating that the mineralocorticoid receptor (MR) plays a role. SP-600125 (3 μM)—a selective inhibitor of c-Jun NH2-terminal kinase (JNK)—inhibited aldosterone-induced apoptosis in ARVM. Although aldosterone increased the expression of both stress-activated protein kinases, pretreatment with fenofibrate (10 μM) decreased aldosterone-mediated apoptosis by inhibiting only JNK phosphorylation and the aldosterone-induced increases in Bax, p53, and cleaved caspase-3 and decreases in Bcl-2 protein expression in ARVM. In vivo studies demonstrated that chronic fenofibrate (100 mg·kg body wt−1·day−1) inhibited myocardial Bax and increased Bcl-2 expression in aldosterone-induced cardiac hypertrophy. Similarly, eplerenone, a selective MR inhibitor, used in chronic pressure-overload ascending aortic constriction inhibited myocardial Bax expression but had no effect on Bcl-2 expression. Therefore, involvement of JNK MAPK-dependent mitochondrial death pathway mediates ARVM aldosterone-induced apoptosis and is inhibited by fenofibrate, a peroxisome proliferator-activated receptor (PPAR)α ligand. Fenofibrate mediates beneficial effects in cardiac remodeling by inhibiting programmed cell death and the stress-activated kinases. PMID:19395558

No prolongation of skin allograft survival by immunoproteasome inhibition in mice.

PubMed

Mundt, Sarah; Basler, Michael; Sawitzki, Birgit; Groettrup, Marcus

2017-08-01

The immunoproteasome, a distinct class of proteasomes, which is inducible under inflammatory conditions and constitutively expressed in monocytes and lymphocytes, is known to shape the antigenic repertoire presented on major histocompatibility complex (MHC) class I molecules. Moreover, inhibition of the immunoproteasome subunit LMP7 ameliorates clinical symptoms of autoimmune diseases in vivo and was shown to suppress the development of T helper cell (Th) 1 and Th17 cells and to promote regulatory T-cell (Treg) generation independently of its function in antigen processing. Since Th1 and Th17 cells are detrimental and Treg cells are critical for transplant acceptance, we investigated the influence of the LMP7-selective inhibitor ONX 0914 in a mixed lymphocyte reaction (MLR) in vitro as well as on allograft rejection in a MHC-disparate (C57BL/6 to BALB/c) and a multiple minor histocompatibility antigen (miHA)-disparate (B10.Br to C3H) model of skin transplantation in vivo. Although we observed reduced allo-specific IL-17 production of T cells in vitro, we found that selective inhibition of LMP7 had neither an influence on allograft survival in an MHC-mismatch model nor in a multiple minor mismatch skin transplantation model. We conclude that inhibition of the immunoproteasome is not effective in prolonging skin allograft survival in skin allotransplantation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Natural Docosahexaenoic Acid in the Triglyceride Form Attenuates In Vitro Microglial Activation and Ameliorates Autoimmune Encephalomyelitis in Mice.

PubMed

Mancera, Pilar; Wappenhans, Blanca; Cordobilla, Begoña; Virgili, Noemí; Pugliese, Marco; Rueda, Fèlix; Espinosa-Parrilla, Juan F; Domingo, Joan C

2017-06-30

Many neurodegenerative diseases are associated, at least in part, to an inflammatory process in which microglia plays a major role. The effect of the triglyceride form of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (TG-DHA) was assayed in vitro and in vivo to assess the protective and anti-inflammatory activity of this compound. In the in vitro study, BV-2 microglia cells were previously treated with TG-DHA and then activated with Lipopolysaccharide (LPS) and Interferon-gamma (IFN-γ). TG-DHA treatment protected BV-2 microglia cells from oxidative stress toxicity attenuating NO production and suppressing the induction of inflammatory cytokines. When compared with DHA in the ethyl-ester form, a significant difference in the ability to inhibit NO production in favor of TG-DHA was observed. TG-DHA inhibited significantly splenocyte proliferation but isolated CD4+ lymphocyte proliferation was unaffected. In a mice model of autoimmune encephalomyelitis (EAE), 250 mg/kg/day oral TG-DHA treatment was associated with a significant amelioration of the course and severity of the disease as compared to untreated animals. TG-DHA-treated EAE mice showed a better weight profile, which is a symptom related to a better course of encephalomyelitis. TG-DHA may be a promising therapeutic agent in neuroinflammatory processes and merit to be more extensively studied in human neurodegenerative disorders.

Blonanserin ameliorates phencyclidine-induced visual-recognition memory deficits: the complex mechanism of blonanserin action involving D₃-5-HT₂A and D₁-NMDA receptors in the mPFC.

PubMed

Hida, Hirotake; Mouri, Akihiro; Mori, Kentaro; Matsumoto, Yurie; Seki, Takeshi; Taniguchi, Masayuki; Yamada, Kiyofumi; Iwamoto, Kunihiro; Ozaki, Norio; Nabeshima, Toshitaka; Noda, Yukihiro

2015-02-01

Blonanserin differs from currently used serotonin 5-HT₂A/dopamine-D₂ receptor antagonists in that it exhibits higher affinity for dopamine-D₂/₃ receptors than for serotonin 5-HT₂A receptors. We investigated the involvement of dopamine-D₃ receptors in the effects of blonanserin on cognitive impairment in an animal model of schizophrenia. We also sought to elucidate the molecular mechanism underlying this involvement. Blonanserin, as well as olanzapine, significantly ameliorated phencyclidine (PCP)-induced impairment of visual-recognition memory, as demonstrated by the novel-object recognition test (NORT) and increased extracellular dopamine levels in the medial prefrontal cortex (mPFC). With blonanserin, both of these effects were antagonized by DOI (a serotonin 5-HT₂A receptor agonist) and 7-OH-DPAT (a dopamine-D₃ receptor agonist), whereas the effects of olanzapine were antagonized by DOI but not by 7-OH-DPAT. The ameliorating effect was also antagonized by SCH23390 (a dopamine-D₁ receptor antagonist) and H-89 (a protein kinase A (PKA) inhibitor). Blonanserin significantly remediated the decrease in phosphorylation levels of PKA at Thr(197) and of NR1 (an essential subunit of N-methyl-D-aspartate (NMDA) receptors) at Ser(897) by PKA in the mPFC after a NORT training session in the PCP-administered mice. There were no differences in the levels of NR1 phosphorylated at Ser(896) by PKC in any group. These results suggest that the ameliorating effect of blonanserin on PCP-induced cognitive impairment is associated with indirect functional stimulation of the dopamine-D₁-PKA-NMDA receptor pathway following augmentation of dopaminergic neurotransmission due to inhibition of both dopamine-D₃ and serotonin 5-HT₂A receptors in the mPFC.

Amelioration of an Ultisol profile acidity using crop straws combined with alkaline slag.

PubMed

Li, Jiu-yu; Masud, M M; Li, Zhong-yi; Xu, Ren-kou

2015-07-01

The acidity of Ultisols (pH <5) is detrimental to crop production. Technologies should be explored to promote base saturation and liming effect for amelioration of Ultisol pH. Column leaching experiments were conducted to investigate the amelioration effects of canola straw (CS) and peanut straw (PS) in single treatment and in combination whether with alkaline slag (AS) or with lime on Ultisol profile acidity. The treatment without liming materials was set as control, and the AS and lime in single treatment are set for comparison. Results indicated that all the liming materials increase soil profile pH and soil exchangeable base cations at the 0-40-cm depth, except that the lime had amelioration effect just on 0 to 15-cm profile. The amelioration effect of the liming materials on surface soil acidity was mainly dependent on the ash alkalinity in organic materials or acid neutralization capacity of inorganic materials. Specific adsorption of sulfate (SO4(2-)) or organic anions, decarboxylation of organic acids/anions, and the association of H(+) with organic anions induced a "liming effect" of crop residues and AS on subsoil acidity. Moreover, SO4(2-) and chloride (Cl(-)) in PS, CS, and AS primarily induced base cations to move downward to subsoil and exchange with exchangeable aluminum (Al(3+)) and protons (H(+)). These anions also promoted the exchangeable Al to leach out of the soil profile. The CS was more effective than PS in decreasing soil acidity in the subsoil, which mainly resulted from higher sulfur (S) and Cl content in CS compared to PS. The CS combined with AS was the better amendment choice in practical agricultural systems.

Creatine Monohydrate Enhances Energy Status and Reduces Glycolysis via Inhibition of AMPK Pathway in Pectoralis Major Muscle of Transport-Stressed Broilers.

PubMed

Zhang, Lin; Wang, Xiaofei; Li, Jiaolong; Zhu, Xudong; Gao, Feng; Zhou, Guanghong

2017-08-16

Creatine monohydrate (CMH) contributes to reduce transport-induced muscle rapid glycolysis and improve meat quality of broilers, but the underlying mechanism is still unknown. Therefore, this study aimed to investigate the molecular mechanisms underlying the ameliorative effects of CMH on muscle glycolysis metabolism of transported broilers during summer. The results showed that 3 h transport during summer elevated chicken live weight loss and plasma corticosterone concentration; decreased muscle concentrations of ATP, creatine, and energy charge value; increased muscle AMP concentration and AMP/ATP ratio; and upregulated muscle mRNA expression of LKB1 and AMPKα2, as well as protein expression of p-LKB1 Thr189 and p-AMPKα Thr172 , which subsequently resulted in rapid glycolysis in the pectoralis major muscle and consequent reduction of meat quality. Dietary addition of CMH at 1200 mg/kg ameliorated transport-induced rapid muscle glycolysis and reduction of meat quality via enhancement of the energy-buffering capacity of intramuscular phosphocreatine/creatine system and inhibition of AMPK pathway.

Anti-hyaluronidase Activity in Vitro and Amelioration of Mouse Experimental Dermatitis by Tomato Saponin, Esculeoside A.

PubMed

Zhou, Jian-Rong; Kanda, Yurina; Tanaka, Anna; Manabe, Hideyuki; Nohara, Toshihiro; Yokomizo, Kazumi

2016-01-20

The increasing incidence of atopic dermatitis during recent decades has prompted the development of safe and effective agents for prevention of atopic diseases. Esculeoside A, a glycoside of spirosolane type, is identified as a major component in ripe tomato fruits. The present study investigated the effects of esculeoside A and its aglycon esculeogenin A on hyaluronidase activity in vitro and antiallergy in experimental dermatitis mice. Esculeogenin A/esculeoside A (esculeogenin A equivalent) with an IC50 of about 2 μM/9 μM dose-dependently inhibited hyaluronidase activity measured by a modified Morgan-Elson method. Oral treatment with esculeoside A 10 mg/kg of experimental dermatitis mice for 4 weeks significantly decreased the skin clinical score to 2.5 without any detectable side effects compared with 6.75 of the control. The scratching frequency of esculeoside A 100 mg/kg application was decreased significantly as 107.5 times compared with 296.67 times of the control. Thus, the present study showed that esculeoside A/esculeogenin A significantly blocks hyaluronidase activity in vitro and that esculeoside A ameliorates mouse experimental dermatitis.

Carnosine markedly ameliorates H9N2 swine influenza virus-induced acute lung injury

PubMed Central

Wang, Cunlian; Zhang, Ruihua; Xu, Mingju; Liu, Baojian; Wei, Dong; Wang, Guohua; Tian, Shufei

2015-01-01

Oxidative stress injury is an important pathogenesis of influenza virus in critically ill patients. The present study investigated the efficacy of carnosine, an antioxidant and free radical scavenger, on a model of acute lung injury (ALI) induced by H9N2 swine influenza virus. Female specific-pathogen-free BALB/c mice were randomized into four groups and treated as follows: (1) H9N2 group, (2) mock control group, (3) H9N2+carnosine group and (4) carnosine control group. The H9N2 group mice were inoculated intranasally with A/Swine/Hebei/012/2008/ (H9N2) virus (100 μl) in allantoic fluid (AF), whilst mock-infected animals were intranasally inoculated with non-infectious AF. Carnosine [10 mg (kg body mass)− 1] was administered orally (100 μl) for 7 days consecutively. The survival rate, lung water content, TNF-α and IL-1β levels, lung histopathology, myeloperoxidase (MPO) activity, and Toll-like receptor (TLR)-4 levels were determined at 2, 4, 6, 8 and 14 days after inoculation. Carnosine treatment effectively decreased the mortality (43 versus 75 %, P < 0.05), significantly ameliorated pathological lesions in lungs and decreased the lung wet/dry mass ratio (P < 0.05). It also inhibited MPO activity, suppressed TNF-α and IL-1β release, decreased the H9N2 viral titre, and markedly inhibited levels of TLR-4 mRNA and protein in the lungs of infected mice (P < 0.05), which supported the use of carnosine for managing severe influenza cases. PMID:26233716

Bacoside-A, an Indian Traditional-Medicine Substance, Inhibits β-Amyloid Cytotoxicity, Fibrillation, and Membrane Interactions.

PubMed

Malishev, Ravit; Shaham-Niv, Shira; Nandi, Sukhendu; Kolusheva, Sofiya; Gazit, Ehud; Jelinek, Raz

2017-04-19

Bacoside-A, a family of compounds extracted from the Bacopa monniera plant, is a folk-medicinal substance believed to exhibit therapeutic properties, particularly enhancing cognitive functions and improving memory. We show that bacoside-A exerted significant inhibitory effects upon cytotoxicity, fibrillation, and particularly membrane interactions of amyloid-beta (1-42) (Aβ42), the peptide playing a prominent role in Alzeheimer's disease progression and toxicity. Specifically, preincubation of bacoside-A with Aβ42 significantly reduced cell toxicity and inhibited fibril formation both in buffer solution and, more significantly, in the presence of membrane vesicles. In parallel, spectroscopic and microscopic analyses reveal that bacoside-A blocked membrane interactions of Aβ42, while formation of Aβ42 oligomers was not disrupted. These interesting phenomena suggest that inhibition of Aβ42 oligomer assembly into mature fibrils, and blocking membrane interactions of the oligomers are likely the underlying factors for ameliorating amyloid toxicity by bacoside-A and its putative physiological benefits.

Citric acid inhibits development of cataracts, proteinuria and ketosis in streptozotocin (type1) diabetic rats

PubMed Central

Nagai, Ryoji; Nagai, Mime; Shimasaki, Satoko; Baynes, John W.; Fujiwara, Yukio

2010-01-01

Although many fruits such as lemon and orange contain citric acid, little is known about beneficial effects of citric acid on health. Here we measured the effect of citric acid on the pathogenesis of diabetic complications in streptozotocin-induced diabetic rats. Although oral administration of citric acid to diabetic rats did not affect blood glucose concentration, it delayed the development of cataracts, inhibited accumulation of advanced glycation end products (AGEs) such as Nε-(carboxyethyl)lysine (CEL) and Nε-(carboxymethyl)lysine (CML) in lens proteins, and protected against albuminuria and ketosis . We also show that incubation of protein with acetol, a metabolite formed from acetone by acetone monooxygenase, generate CEL, suggesting that inhibition of ketosis by citric acid may lead to the decrease in CEL in lens proteins. These results demonstrate that the oral administration of citric acid ameliorates ketosis and protects against the development of diabetic complications in an animal model of type 1 diabetes. PMID:20117096

In Vitro and In Vivo Characterization of the Alkaloid Nuciferine.

PubMed

Farrell, Martilias S; McCorvy, John D; Huang, Xi-Ping; Urban, Daniel J; White, Kate L; Giguere, Patrick M; Doak, Allison K; Bernstein, Alison I; Stout, Kristen A; Park, Su Mi; Rodriguiz, Ramona M; Gray, Bradley W; Hyatt, William S; Norwood, Andrew P; Webster, Kevin A; Gannon, Brenda M; Miller, Gary W; Porter, Joseph H; Shoichet, Brian K; Fantegrossi, William E; Wetsel, William C; Roth, Bryan L

2016-01-01

The sacred lotus (Nelumbo nucifera) contains many phytochemicals and has a history of human use. To determine which compounds may be responsible for reported psychotropic effects, we used in silico predictions of the identified phytochemicals. Nuciferine, an alkaloid component of Nelumbo nucifera and Nymphaea caerulea, had a predicted molecular profile similar to antipsychotic compounds. Our study characterizes nuciferine using in vitro and in vivo pharmacological assays. Nuciferine was first characterized in silico using the similarity ensemble approach, and was followed by further characterization and validation using the Psychoactive Drug Screening Program of the National Institute of Mental Health. Nuciferine was then tested in vivo in the head-twitch response, pre-pulse inhibition, hyperlocomotor activity, and drug discrimination paradigms. Nuciferine shares a receptor profile similar to aripiprazole-like antipsychotic drugs. Nuciferine was an antagonist at 5-HT2A, 5-HT2C, and 5-HT2B, an inverse agonist at 5-HT7, a partial agonist at D2, D5 and 5-HT6, an agonist at 5-HT1A and D4 receptors, and inhibited the dopamine transporter. In rodent models relevant to antipsychotic drug action, nuciferine blocked head-twitch responses and discriminative stimulus effects of a 5-HT2A agonist, substituted for clozapine discriminative stimulus, enhanced amphetamine induced locomotor activity, inhibited phencyclidine (PCP)-induced locomotor activity, and rescued PCP-induced disruption of prepulse inhibition without induction of catalepsy. The molecular profile of nuciferine was similar but not identical to that shared with several approved antipsychotic drugs suggesting that nuciferine has atypical antipsychotic-like actions.

Effects of Estradiol on Post-Traumatic Stress Disorder Symptoms

DTIC Science & Technology

2010-03-01

Steroid Metabolism pathways 34 Figure 6. HPG Axis 35 Chapter 3 Figure 1. Effect of 7, 14, and 22 Days of...87 Treatment on Plasma CORT in OVX Sprague-Dawley Rats that were also Immobilization Stressed for 22 -days Figure 3. Effect of Early...for 22 -days Figure 5. Effect of Estradiol, Selective ERα Agonist, and ERβ Agonist 90 Treatment on Pre-Pulse Inhibition in OVX Sprague-Dawley

Rapamycin inhibits epithelial-to-mesenchymal transition of peritoneal mesothelium cells through regulation of Rho GTPases.

PubMed

Xiang, Shilong; Li, Meng; Xie, Xishao; Xie, Zhoutao; Zhou, Qin; Tian, Yuanshi; Lin, Weiqiang; Zhang, Xiaohui; Jiang, Hong; Shou, Zhangfei; Chen, Jianghua

2016-06-01

Epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) is a key process of peritoneal fibrosis. Rapamycin has been previously shown to inhibit EMT of PMCs and prevent peritoneal fibrosis. In this study, we investigated the undefined molecular mechanisms by which rapamycin inhibits EMT of PMCs. To define the protective effect of rapamycin, we initially used a rat PD model which was daily infused with 20 mL of 4.25% high glucose (HG) dialysis solution for 6 weeks to induce fibrosis. The HG rats showed decreased ultrafiltration volume and obvious fibroproliferative response, with markedly increased peritoneal thickness and higher expression of α-smooth muscle actin (α-SMA) and transforming growth factor-β1. Rapamycin significantly ameliorated those pathological changes. Next, we treated rat PMCs with HG to induce EMT and/or rapamycin for indicated time. Rapamycin significantly inhibited HG-induced EMT, which manifests as increased expression of α-SMA, fibronectin, and collagen I, decreased expression of E-cadherin, and increased mobility. HG increased the phosphorylation of PI3K, Akt, and mTOR. Importantly, rapamycin inhibits the RhoA, Rac1, and Cdc42 activated by HG. Moreover, rapamycin repaired the pattern of F-actin distribution induced by HG, reducing the formation of stress fiber, focal adhesion, lamellipodia, and filopodia. Thus, rapamycin shows an obvious protective effect on HG-induced EMT, by inhibiting the activation of Rho GTPases (RhoA, Rac1, and Cdc42). © 2016 Federation of European Biochemical Societies.

Sex-Dependent Psychoneuroendocrine Effects of THC and MDMA in an Animal Model of Adolescent Drug Consumption

PubMed Central

Llorente-Berzal, Alvaro; Puighermanal, Emma; Burokas, Aurelijus; Ozaita, Andrés; Maldonado, Rafael; Marco, Eva M.; Viveros, Maria-Paz

2013-01-01

Ecstasy is a drug that is usually consumed by young people at the weekends and frequently, in combination with cannabis. In the present study we have investigated the long-term effects of administering increasing doses of delta-9-tetrahydrocannabinol [THC; 2.5, 5, 10 mg/kg; i.p.] from postnatal day (pnd) 28 to 45, alone and/or in conjunction with 3,4-methylenedioxymethamphetamine [MDMA; two daily doses of 10 mg/kg every 5 days; s.c.] from pnd 30 to 45, in both male and female Wistar rats. When tested one day after the end of the pharmacological treatment (pnd 46), MDMA administration induced a reduction in directed exploration in the holeboard test and an increase in open-arm exploration in an elevated plus maze. In the long-term, cognitive functions in the novel object test were seen to be disrupted by THC administration to female but not male rats. In the prepulse inhibition test, MDMA-treated animals showed a decrease in prepulse inhibition at the most intense prepulse studied (80 dB), whereas in combination with THC it induced a similar decrease at 75 dB. THC decreased hippocampal Arc expression in both sexes, while in the frontal cortex this reduction was only evident in females. MDMA induced a reduction in ERK1/2 immunoreactivity in the frontal cortex of male but not female animals, and THC decreased prepro-orexin mRNA levels in the hypothalamus of males, although this effect was prevented when the animals also received MDMA. The results presented indicate that adolescent exposure to THC and/or MDMA induces long-term, sex-dependent psychophysiological alterations and they reveal functional interactions between the two drugs. PMID:24223797

Diallyl trisulfide ameliorates myocardial ischemia-reperfusion injury by reducing oxidative stress and endoplasmic reticulum stress-mediated apoptosis in type 1 diabetic rats: role of SIRT1 activation.

PubMed

Yu, Liming; Li, Shu; Tang, Xinlong; Li, Zhi; Zhang, Jian; Xue, Xiaodong; Han, Jinsong; Liu, Yu; Zhang, Yuji; Zhang, Yong; Xu, Yinli; Yang, Yang; Wang, Huishan

2017-07-01

Diallyl trisulfide (DATS) protects against apoptosis during myocardial ischemia-reperfusion (MI/R) injury in diabetic state, although the underlying mechanisms remain poorly defined. Previously, we and others demonstrated that silent information regulator 1 (SIRT1) activation inhibited oxidative stress and endoplasmic reticulum (ER) stress during MI/R injury. We hypothesize that DATS reduces diabetic MI/R injury by activating SIRT1 signaling. Streptozotocin (STZ)-induced type 1 diabetic rats were subjected to MI/R surgery with or without perioperative administration of DATS (40 mg/kg). We found that DATS treatment markedly improved left ventricular systolic pressure and the first derivative of left ventricular pressure, reduced myocardial infarct size as well as serum creatine kinase and lactate dehydrogenase activities. Furthermore, the myocardial apoptosis was also suppressed by DATS as evidenced by reduced apoptotic index and cleaved caspase-3 expression. However, these effects were abolished by EX527 (the inhibitor of SIRT1 signaling, 5 mg/kg). We further found that DATS effectively upregulated SIRT1 expression and its nuclear distribution. Additionally, PERK/eIF2α/ATF4/CHOP-mediated ER stress-induced apoptosis was suppressed by DATS treatment. Moreover, DATS significantly activated Nrf-2/HO-1 antioxidant signaling pathway, thus reducing Nox-2/4 expressions. However, the ameliorative effects of DATS on oxidative stress and ER stress-mediated myocardial apoptosis were inhibited by EX527 administration. Taken together, these data suggest that perioperative DATS treatment effectively ameliorates MI/R injury in type 1 diabetic setting by enhancing cardiac SIRT1 signaling. SIRT1 activation not only upregulated Nrf-2/HO-1-mediated antioxidant signaling pathway but also suppressed PERK/eIF2α/ATF4/CHOP-mediated ER stress level, thus reducing myocardial apoptosis and eventually preserving cardiac function.

Baicalin Ameliorates Liver Injury Induced by Chronic plus Binge Ethanol Feeding by Modulating Oxidative Stress and Inflammation via CYP2E1 and NRF2 in Mice

PubMed Central

He, Ping; Wu, Yafeng; Shun, Jianchao; Liang, Yaodong; Cheng, Mingliang

2017-01-01

Alcoholic liver injury leads to serious complication including death. The potential role of baicalin at the transcription level in mice model of alcohol injury is not known yet. In this study, we examined the effect of baicalin against chronic plus binge ethanol model in mice and understanding the mechanism of protection. Liver function, histology, steatosis, inflammation, NF-κB activity, oxidative stress sources, nuclear translocation of NRF2 transcription factor, and cell death were assessed. Treatment with baicalin ameliorated ethanol-induced oxidative stress, inflammation, and cell death. Baicalin attenuated ethanol-induced proinflammatory molecules such as TNF-α, IL-1β, MIP-2, and MCP-1 and reversed redox-sensitive transcription factor NF-κB activation. Baicalin also modulated Kupffer cell activation in vitro. Baicalin inhibited ethanol-induced expression of reactive oxygen species (ROS) generating enzymes NOX2, p67phox, xanthine oxidase, and iNOS in addition to CYP2E1 activities. Baicalin also enhanced ethanol-induced NRF2 nuclear translocation and increased downstream target gene HO-1 as antioxidant defense. Finally, baicalin reduced significant apoptotic and necrotic cell death. Our study suggests that baicalin ameliorates chronic plus binge ethanol-induced liver injury involving molecular crosstalk of multiple pathways at the transcriptional level and through upregulation of antioxidant defense mechanism. PMID:28951767

Hypothalamic AMPK-induced autophagy ameliorates hypercatabolism in septic rats by regulating POMC expression.

PubMed

Cao, Chun; Gao, Tao; Cheng, Yan; Cheng, Minhua; Su, Ting; Xi, Fengchan; Wu, Cuili; Yu, Wenkui

2018-03-18

Hypercatabolism plays a critical role in the pathogenesis of post-critical care debility in critical patients. Central nervous system may exerte a critical role in the regulation of hypercatabolism. However, little is known about the exact mechanisms of the central role. Here, we reported that actived hypothalamic AMP-activated protein kinase (AMPK)-induced autophagy modulated the expression of POMC to ameliorate hypercatabolism in septic rats. Firstly, rats were i.c.v. injected with the lentiviral vector containing shRNA against POMC. Two weeks after injections, rats were intraperitoneally injected with LPS or saline. Twenty-four hours later, blood, skeletal muscle and hypothalamus tissues were obtained. Hypercatabolism markers and neuropeptides expression were detected. Then, rats were injected with AICAR or saline into third ventricle and promptly intraperitoneally injected with LPS or saline. Twenty-four hours after infection, blood, skeletal muscle and hypothalamus tissues were obtained. Hypercatabolism, hypothalamic AMPK-induced autophagy markers and neuropeptides expression were also detected. Results showed that sepsis would decrease the level of hypothalamic autophagy accompany with the alterations of POMC expression and hypercatabolism. Knocking out hypothalamus POMC expression could significantly ameliorate hypercatabolism. Moreover, Central activation of AMPK-induced autophagy pathway via third ventricle injection of AICAR, an AMPK activator, could efficiently ameliorate hypercatabolism as well as attenuate the elevated POMC expression rather than other neuropeptides. Taken together, these results suggested that hypothalamic AMPK-autophagy pathway as a regulatory pathway for POMC expression was essential for hypercatabolism during sepsis. And hypothalamic AMPK-autophagy activation could attenuate the POMC expression to ameliorate hypercatabolism. Pharmaceuticals with the ability of activating hypothalamic AMPK-autophagy pathway may be a therapeutic

Renin-angiotensin system inhibition ameliorates CCl4-induced liver fibrosis in mice through the inactivation of nuclear transcription factor kappa B.

PubMed

Saber, Sameh; Mahmoud, Amr A A; Helal, Noha S; El-Ahwany, Eman; Abdelghany, Rasha H

2018-06-01

Therapeutic interventions for liver fibrosis are still limited due to the complicated molecular pathogenesis. Renin-angiotensin system (RAS) seems to contribute to the development of hepatic fibrosis. Therefore, we aimed to examine the effect of RAS inhibition on CCl 4 -induced liver fibrosis. Mice were treated with silymarin (30 mg·kg -1 ), perindopril (1 mg·kg -1 ), fosinopril (2 mg·kg -1 ), or losartan (10 mg·kg -1 ). The administration of RAS inhibitors improved liver histology and decreased protein expression of alpha smooth muscle actin (α-SMA) and hepatic content of hydroxyproline. These effects found to be mediated via inactivation of nuclear transcription factor kappa B (NFκB) pathway by the inhibition of NFκB p65 phosphorylation at the Ser536 residue and phosphorylation-induced degradation of nuclear factor kappa-B inhibitor alpha (NFκBia) subsequently inhibited NFκB-induced TNF-α and TGF-β1, leading to lower levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and vascular endothelial growth factor (VEGF). We concluded that the tissue affinity of the angiotensin converting enzyme inhibitors (ACEIs) has no impact on its antifibrotic activity and that interfering the RAS either through the inhibition of ACE or the blockade of AT1R has the same therapeutic benefit. These results suggest RAS inhibitors as promising candidates for further clinical trials in the management of hepatic fibrosis.

Plecanatide and dolcanatide, novel guanylate cyclase-C agonists, ameliorate gastrointestinal inflammation in experimental models of murine colitis.

PubMed

Shailubhai, Kunwar; Palejwala, Vaseem; Arjunan, Krishna Priya; Saykhedkar, Sayali; Nefsky, Bradley; Foss, John A; Comiskey, Stephen; Jacob, Gary S; Plevy, Scott E

2015-11-06

To evaluate the effect of orally administered plecanatide or dolcanatide, analogs of uroguanylin, on amelioration of colitis in murine models. The cyclic guanosine monophosphate (cGMP) stimulatory potency of plecanatide and dolcanatide was measured using a human colon carcinoma T84 cell-based assay. For animal studies all test agents were formulated in phosphate buffered saline. Sulfasalazine or 5-amino salicylic acid (5-ASA) served as positive controls. Effect of oral treatment with test agents on amelioration of acute colitis induced either by dextran sulfate sodium (DSS) in drinking water or by rectal instillation of trinitrobenzene sulfonic (TNBS) acid, was examined in BALB/c and/or BDF1 mice. Additionally, the effect of orally administered plecanatide on the spontaneous colitis in T-cell receptor alpha knockout (TCRα(-/-)) mice was also examined. Amelioration of colitis was assessed by monitoring severity of colitis, disease activity index and by histopathology. Frozen colon tissues were used to measure myeloperoxidase activity. Plecanatide and dolcanatide are structurally related analogs of uroguanylin, which is an endogenous ligand of guanylate cyclase-C (GC-C). As expected from the agonists of GC-C, both plecanatide and dolcanatide exhibited potent cGMP-stimulatory activity in T84 cells. Once-daily treatment by oral gavage with either of these analogs (0.05-0.5 mg/kg) ameliorated colitis in both DSS and TNBS-induced models of acute colitis, as assessed by body weight, reduction in colitis severity (P < 0.05) and disease activity index (P < 0.05). Amelioration of colitis by either of the drug candidates was comparable to that achieved by orally administered sulfasalazine or 5-ASA. Plecanatide also effectively ameliorated colitis in TCRα(-/-) mice, a model of spontaneous colitis. As dolcanatide exhibited higher resistance to proteolysis in simulated gastric and intestinal juices, it was selected for further studies. This is the first-ever study reporting

Plecanatide and dolcanatide, novel guanylate cyclase-C agonists, ameliorate gastrointestinal inflammation in experimental models of murine colitis

PubMed Central

Shailubhai, Kunwar; Palejwala, Vaseem; Arjunan, Krishna Priya; Saykhedkar, Sayali; Nefsky, Bradley; Foss, John A; Comiskey, Stephen; Jacob, Gary S; Plevy, Scott E

2015-01-01

AIM: To evaluate the effect of orally administered plecanatide or dolcanatide, analogs of uroguanylin, on amelioration of colitis in murine models. METHODS: The cyclic guanosine monophosphate (cGMP) stimulatory potency of plecanatide and dolcanatide was measured using a human colon carcinoma T84 cell-based assay. For animal studies all test agents were formulated in phosphate buffered saline. Sulfasalazine or 5-amino salicylic acid (5-ASA) served as positive controls. Effect of oral treatment with test agents on amelioration of acute colitis induced either by dextran sulfate sodium (DSS) in drinking water or by rectal instillation of trinitrobenzene sulfonic (TNBS) acid, was examined in BALB/c and/or BDF1 mice. Additionally, the effect of orally administered plecanatide on the spontaneous colitis in T-cell receptor alpha knockout (TCRα-/-) mice was also examined. Amelioration of colitis was assessed by monitoring severity of colitis, disease activity index and by histopathology. Frozen colon tissues were used to measure myeloperoxidase activity. RESULTS: Plecanatide and dolcanatide are structurally related analogs of uroguanylin, which is an endogenous ligand of guanylate cyclase-C (GC-C). As expected from the agonists of GC-C, both plecanatide and dolcanatide exhibited potent cGMP-stimulatory activity in T84 cells. Once-daily treatment by oral gavage with either of these analogs (0.05-0.5 mg/kg) ameliorated colitis in both DSS and TNBS-induced models of acute colitis, as assessed by body weight, reduction in colitis severity (P < 0.05) and disease activity index (P < 0.05). Amelioration of colitis by either of the drug candidates was comparable to that achieved by orally administered sulfasalazine or 5-ASA. Plecanatide also effectively ameliorated colitis in TCRα-/- mice, a model of spontaneous colitis. As dolcanatide exhibited higher resistance to proteolysis in simulated gastric and intestinal juices, it was selected for further studies. CONCLUSION: This is

Agmatine ameliorates atherosclerosis progression and endothelial dysfunction in high cholesterol-fed rabbits.

PubMed

El-Awady, Mohammed S; Suddek, Ghada M

2014-06-01

The aim of this work was to explore possible effects of agmatine, an endogenous inhibitor of inducible nitric oxide synthase (iNOS), against hypercholesterolemia-induced lipid profile changes and endothelial dysfunction. Hypercholesterolemia was induced by feeding rabbits with a high-cholesterol diet (HCD, 0.5%) for 8 weeks. Another HCD-fed group was orally administered agmatine (10 mg/kg/day) during weeks 5 through 8. Serum lipid profile, malondialdehyde (MDA), nitric oxide (NO) and lactate dehydrogenase (LDH) were determined. Aorta was isolated to analyse vascular reactivity, atherosclerotic lesions and intima/media (I/M) ratio. HCD induced a significant increase in serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides and high-density lipoprotein cholesterol (HDL-C). Agmatine administration significantly decreased HCD-induced elevations in serum TC and LDL-C, MDA, LDH and NO while significantly increased HDL-C levels. Additionally, agmatine significantly protected against HCD-induced attenuation of rabbit aortic endothelium-dependent relaxation to acetylcholine. HCD and agmatine did not significantly influence aortic endothelium-independent relaxation to sodium nitroprusside. Moreover, agmatine significantly reduced the elevation in aortic atherosclerotic lesion area and I/M ratio. This study is the first to reveal that agmatine has the ability to ameliorate hypercholesterolemia-induced lipemic-oxidative and endothelial function injuries possibly by its antioxidant potential and/or iNOS inhibition. © 2014 Royal Pharmaceutical Society.

Small-molecule inhibitors of FABP4/5 ameliorate dyslipidemia but not insulin resistance in mice with diet-induced obesity

PubMed Central

Lan, Hong; Cheng, Cliff C.; Kowalski, Timothy J.; Pang, Ling; Shan, Lixin; Chuang, Cheng-Chi; Jackson, James; Rojas-Triana, Alberto; Bober, Loretta; Liu, Li; Voigt, Johannes; Orth, Peter; Yang, Xianshu; Shipps, Gerald W.; Hedrick, Joseph A.

2011-01-01

Fatty acid binding protein-4 (FABP4) and FABP5 are two closely related FA binding proteins expressed primarily in adipose tissue and/or macrophages. The small-molecule FABP4 inhibitor BMS309403 was previously reported to improve insulin sensitivity in leptin-deficient Lepob/Lepob (ob/ob) mice. However, this compound was not extensively characterized in the more physiologically relevant animal model of mice with diet-induced obesity (DIO). Here, we report the discovery and characterization of a novel series of FABP4/5 dual inhibitors represented by Compounds 1–3. Compared with BMS309403, the compounds had significant in vitro potency toward both FABP4 and FABP5. In cell-based assays, Compounds 2 and 3 were more potent than BMS309403 to inhibit lipolysis in 3T3-L1 adipocytes and in primary human adipocytes. They also inhibited MCP-1 release from THP-1 macrophages as well as from primary human macrophages. When chronically administered to DIO mice, BMS309403 and Compound 3 reduced plasma triglyceride and free FA levels. Compound 3 reduced plasma free FAs at a lower dose level than BMS309403. However, no significant change was observed in insulin, glucose, or glucose tolerance. Our results indicate that the FABP4/5 inhibitors ameliorate dyslipidemia but not insulin resistance in DIO mice. PMID:21296956

Small-molecule inhibitors of FABP4/5 ameliorate dyslipidemia but not insulin resistance in mice with diet-induced obesity.

PubMed

Lan, Hong; Cheng, Cliff C; Kowalski, Timothy J; Pang, Ling; Shan, Lixin; Chuang, Cheng-Chi; Jackson, James; Rojas-Triana, Alberto; Bober, Loretta; Liu, Li; Voigt, Johannes; Orth, Peter; Yang, Xianshu; Shipps, Gerald W; Hedrick, Joseph A

2011-04-01

Fatty acid binding protein-4 (FABP4) and FABP5 are two closely related FA binding proteins expressed primarily in adipose tissue and/or macrophages. The small-molecule FABP4 inhibitor BMS309403 was previously reported to improve insulin sensitivity in leptin-deficient Lep(ob)/Lep(ob) (ob/ob) mice. However, this compound was not extensively characterized in the more physiologically relevant animal model of mice with diet-induced obesity (DIO). Here, we report the discovery and characterization of a novel series of FABP4/5 dual inhibitors represented by Compounds 1-3. Compared with BMS309403, the compounds had significant in vitro potency toward both FABP4 and FABP5. In cell-based assays, Compounds 2 and 3 were more potent than BMS309403 to inhibit lipolysis in 3T3-L1 adipocytes and in primary human adipocytes. They also inhibited MCP-1 release from THP-1 macrophages as well as from primary human macrophages. When chronically administered to DIO mice, BMS309403 and Compound 3 reduced plasma triglyceride and free FA levels. Compound 3 reduced plasma free FAs at a lower dose level than BMS309403. However, no significant change was observed in insulin, glucose, or glucose tolerance. Our results indicate that the FABP4/5 inhibitors ameliorate dyslipidemia but not insulin resistance in DIO mice.

Structural basis of kynurenine 3-monooxygenase inhibition

PubMed Central

Amaral, Marta; Levy, Colin; Heyes, Derren J.; Lafite, Pierre; Outeiro, Tiago F.; Giorgini, Flaviano; Leys, David; Scrutton, Nigel S.

2013-01-01

Inhibition of kynurenine 3-monooxygenase (KMO), an enzyme in the eukaryotic tryptophan catabolic pathway (i.e. kynurenine pathway), leads to amelioration of Huntington’s disease-relevant phenotypes in yeast, fruit fly, and mouse models1–5, as well as a mouse model of Alzheimer’s disease3. KMO is a FAD-dependent monooxygenase, and is located in the outer mitochondrial membrane where it converts L-kynurenine to 3-hydroxykynurenine. Perturbations in the levels of kynurenine pathway metabolites have been linked to the pathogenesis of a spectrum of brain disorders6, as well as cancer7,8, and several peripheral inflammatory conditions9. Despite the importance of KMO as a target for neurodegenerative disease, the molecular basis of KMO inhibition by available lead compounds has remained hitherto unknown. Here we report the first crystal structure of KMO, in the free form and in complex with the tight-binding inhibitor UPF 648. UPF 648 binds close to the FAD cofactor and perturbs the local active site structure, preventing productive binding of the substrate kynurenine. Functional assays and targeted mutagenesis revealed that the active site architecture and UPF 648 binding are essentially identical in human KMO, validating the yeast KMO:UPF 648 structure as a template for structure-based drug design. This will inform the search for new KMO inhibitors that are able to cross the blood-brain barrier in targeted therapies against neurodegenerative diseases such as Huntington’s, Alzheimer’s, and Parkinson’s diseases. PMID:23575632

Structural basis of kynurenine 3-monooxygenase inhibition.

PubMed

Amaral, Marta; Levy, Colin; Heyes, Derren J; Lafite, Pierre; Outeiro, Tiago F; Giorgini, Flaviano; Leys, David; Scrutton, Nigel S

2013-04-18

Inhibition of kynurenine 3-monooxygenase (KMO), an enzyme in the eukaryotic tryptophan catabolic pathway (that is, kynurenine pathway), leads to amelioration of Huntington's-disease-relevant phenotypes in yeast, fruitfly and mouse models, as well as in a mouse model of Alzheimer's disease. KMO is a flavin adenine dinucleotide (FAD)-dependent monooxygenase and is located in the outer mitochondrial membrane where it converts l-kynurenine to 3-hydroxykynurenine. Perturbations in the levels of kynurenine pathway metabolites have been linked to the pathogenesis of a spectrum of brain disorders, as well as cancer and several peripheral inflammatory conditions. Despite the importance of KMO as a target for neurodegenerative disease, the molecular basis of KMO inhibition by available lead compounds has remained unknown. Here we report the first crystal structure of Saccharomyces cerevisiae KMO, in the free form and in complex with the tight-binding inhibitor UPF 648. UPF 648 binds close to the FAD cofactor and perturbs the local active-site structure, preventing productive binding of the substrate l-kynurenine. Functional assays and targeted mutagenesis reveal that the active-site architecture and UPF 648 binding are essentially identical in human KMO, validating the yeast KMO-UPF 648 structure as a template for structure-based drug design. This will inform the search for new KMO inhibitors that are able to cross the blood-brain barrier in targeted therapies against neurodegenerative diseases such as Huntington's, Alzheimer's and Parkinson's diseases.

MHY1485 ameliorates UV-induced skin cell damages via activating mTOR-Nrf2 signaling

PubMed Central

Yang, Bo; Xu, Qiu-Yun; Guo, Chun-Yan; Huang, Jin-Wen; Wang, Shu-Mei; Li, Yong-Mei; Tu, Ying; He, Li; Bi, Zhi-Gang; Ji, Chao; Cheng, Bo

2017-01-01

Ultra Violet (UV)-caused skin cell damage is a main cause of skin cancer. Here, we studied the activity of MHY1485, a mTOR activator, in UV-treated skin cells. In primary human skin keratinocytes, HaCaT keratinocytes and human skin fibroblasts, MHY1485 ameliorated UV-induced cell death and apoptosis. mTOR activation is required for MHY1485-induced above cytoprotective actions. mTOR kinase inhibitors (OSI-027, AZD-8055 and AZD-2014) or mTOR shRNA knockdown almost abolished MHY1485-induced cytoprotection. Further, MHY1485 treatment in skin cells activated mTOR downstream NF-E2-related factor 2 (Nrf2) signaling, causing Nrf2 Ser-40 phosphorylation, stabilization/upregulation and nuclear translocation, as well as mRNA expression of Nrf2-dictated genes. Contrarily, Nrf2 knockdown or S40T mutation almost nullified MHY1485-induced cytoprotection. MHY1485 suppressed UV-induced reactive oxygen species production and DNA single strand breaks in skin keratinocytes and fibroblasts. Together, we conclude that MHY1485 inhibits UV-induced skin cell damages via activating mTOR-Nrf2 signaling. PMID:28061443

Adiponectin inhibits leptin-induced oncogenic signalling in oesophageal cancer cells by activation of PTP1B.

PubMed

Beales, Ian L P; Garcia-Morales, Carla; Ogunwobi, Olorunseun O; Mutungi, Gabriel

2014-01-25

Obesity is characterised by hyperleptinaemia and hypoadiponectinaemia and these metabolic abnormalities may contribute to the progression of several obesity-associated cancers including oesophageal adenocarcinoma (OAC). We have examined the effects of leptin and adiponectin on OE33 OAC cells. Leptin stimulated proliferation, invasion and migration and inhibited apoptosis in a STAT3-dependant manner. Leptin-stimulated MMP-2 secretion in a partly STAT3-dependent manner and MMP-9 secretion via a STAT3-independent pathway. Adiponectin inhibited leptin-induced proliferation, migration, invasion, MMP secretion and reduced the anti-apoptotic effects: these effects of adiponectin were ameliorated by both a non-specific tyrosine phosphatase inhibitor and a specific PTP1B inhibitor. Adiponectin reduced leptin-stimulated JAK2 activation and STAT3 transcriptional activity in a PTP1B-sensitive manner and adiponectin increased both PTP1B protein and activity. We conclude that adiponectin restrains leptin-induced signalling and pro-carcinogenic behaviour by inhibiting the early events in leptin-induced signal transduction by activating PTP1B. Relative adiponectin deficiency in obesity may contribute to the promotion of OAC. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

XuefuZhuyu decoction protected cardiomyocytes against hypoxia/reoxygenation injury by inhibiting autophagy.

PubMed

Shi, Xiaowen; Zhu, Haiyan; Zhang, Yuanyuan; Zhou, Mingmei; Tang, Danli; Zhang, Huamin

2017-06-19

XuefuZhuyu decoction (XFZY) is a well-known traditional Chinese herbal medicine for the treatment of various cardiovascular diseases, such as unstable angina pectoris and myocardial ischemia-reperfusion injury. However, the mechanism by which XFZY contributes to the amelioration of cardiac injury remains unclear. H9C2 cells were cultured under the hypoxic condition for 10 h and reoxygenated for 2 h. In the presence of various concentrations of XFZY for 12 h, the cell viability was measured by MTT assay. The protective effect of XFZY in hypoxia/reoxygenation (H/R) cell model was confirmed by measuring the amount of LDH released into the extracellular fluid. Cell apoptosis was measured by western blotting. The autophagy level of H9C2 cells and the correlative pathway were determined by transmission electron microscopy, Cyto-ID® Autophagy Detection Kit, and western blotting. In this study, we investigated the effects of XFZY on H/R induced cardiac injury. The results showed that treatment with XFZY significantly inhibited autophagy induced by H/R, with decreased formation of autophagosomes as well as the expression of LC3-II/LC3-I ratio and Beclin 1 after H/R. Importantly, inhibition of autophagy by XFZY resulted in enhanced cell viability and decreased apoptosis. XFZY also inhibited the activation of AMPK and upregulated the phosphorylation of mammalian target of Rapamycin (mTOR). The cardioprotective effects of XFZY during H/R were mediated by inhibiting autophagy via regulating AMPK-mTOR signaling pathways.

Reduction of EEG Theta Power and Changes in Motor Activity in Rats Treated with Ceftriaxone

PubMed Central

Bellesi, Michele; Vyazovskiy, Vladyslav V.; Tononi, Giulio; Cirelli, Chiara; Conti, Fiorenzo

2012-01-01

The glutamate transporter GLT-1 is responsible for the largest proportion of total glutamate transport. Recently, it has been demonstrated that ceftriaxone (CEF) robustly increases GLT-1 expression. In addition, physiological studies have shown that GLT-1 up-regulation strongly affects synaptic plasticity, and leads to an impairment of the prepulse inhibition, a simple form of information processing, thus suggesting that GLT-1 over-expression may lead to dysfunctions of large populations of neurons. To test this possibility, we assessed whether CEF affects cortical electrical activity by using chronic electroencephalographic (EEG) recordings in male WKY rats. Spectral analysis showed that 8 days of CEF treatment resulted in a delayed reduction in EEG theta power (7–9 Hz) in both frontal and parietal derivations. This decrease peaked at day 10, i.e., 2 days after the end of treatment, and disappeared by day 16. In addition, we found that the same CEF treatment increased motor activity, especially when EEG changes are more prominent. Taken together, these data indicate that GLT-1 up-regulation, by modulating glutamatergic transmission, impairs the activity of widespread neural circuits. In addition, the increased motor activity and prepulse inhibition alterations previously described suggest that neural circuits involved in sensorimotor control are particularly sensitive to GLT-1 up-regulation. PMID:22479544

Reduction of EEG theta power and changes in motor activity in rats treated with ceftriaxone.

PubMed

Bellesi, Michele; Vyazovskiy, Vladyslav V; Tononi, Giulio; Cirelli, Chiara; Conti, Fiorenzo

2012-01-01

The glutamate transporter GLT-1 is responsible for the largest proportion of total glutamate transport. Recently, it has been demonstrated that ceftriaxone (CEF) robustly increases GLT-1 expression. In addition, physiological studies have shown that GLT-1 up-regulation strongly affects synaptic plasticity, and leads to an impairment of the prepulse inhibition, a simple form of information processing, thus suggesting that GLT-1 over-expression may lead to dysfunctions of large populations of neurons. To test this possibility, we assessed whether CEF affects cortical electrical activity by using chronic electroencephalographic (EEG) recordings in male WKY rats. Spectral analysis showed that 8 days of CEF treatment resulted in a delayed reduction in EEG theta power (7-9 Hz) in both frontal and parietal derivations. This decrease peaked at day 10, i.e., 2 days after the end of treatment, and disappeared by day 16. In addition, we found that the same CEF treatment increased motor activity, especially when EEG changes are more prominent. Taken together, these data indicate that GLT-1 up-regulation, by modulating glutamatergic transmission, impairs the activity of widespread neural circuits. In addition, the increased motor activity and prepulse inhibition alterations previously described suggest that neural circuits involved in sensorimotor control are particularly sensitive to GLT-1 up-regulation.

Brief postnatal exposure to phenobarbital impairs passive-avoidance learning and sensorimotor gating in rats

PubMed Central

Gutherz, Samuel B.; Kulick, Catherine V.; Soper, Colin; Kondratyev, Alexei; Gale, Karen; Forcelli, Patrick A.

2014-01-01

Phenobarbital is the most commonly utilized drug for the treatment of neonatal seizures. However, mounting preclinical evidence suggests that even brief exposure to phenobarbital in the neonatal period can induce neuronal apoptosis, alterations in synaptic development, and long-lasting changes in behavioral functions. In the present report, we treated neonatal rat pups with phenobarbital and evaluated behavior in adulthood. Pups were treated initially with a loading dose (80mg/kg) on postnatal day (P)7 and with a lower dose (40 mg/kg) on P8 and P9. We examined sensorimotor gating (prepulse inhibition), passive avoidance, and conditioned place preference to cocaine when the animals reached adulthood. Consistent with our previous reports, we found that three days of neonatal exposure to phenobarbital significantly impaired prepulse inhibition as compared to vehicle-exposed control animals. Using a step-though passive avoidance paradigm, we found that animals exposed to phenobarbital as neonates and tested as adults showed significant deficits in passive avoidance retention as compared to matched controls, indicating impairment in associative memory and/or recall. Finally, we examined place preference conditioning in response to cocaine. Phenobarbital exposure did not alter the normal conditioned place preference associated with cocaine exposure. Our findings expand the profile of behavioral toxicity induced by phenobarbital. PMID:25112558

Brief postnatal exposure to phenobarbital impairs passive avoidance learning and sensorimotor gating in rats.

PubMed

Gutherz, Samuel B; Kulick, Catherine V; Soper, Colin; Kondratyev, Alexei; Gale, Karen; Forcelli, Patrick A

2014-08-01

Phenobarbital is the most commonly utilized drug for the treatment of neonatal seizures. However, mounting preclinical evidence suggests that even brief exposure to phenobarbital in the neonatal period can induce neuronal apoptosis, alterations in synaptic development, and long-lasting changes in behavioral functions. In the present report, we treated neonatal rat pups with phenobarbital and evaluated behavior in adulthood. Pups were treated initially with a loading dose (80 mg/kg) on postnatal day (P)7 and with a lower dose (40 mg/kg) on P8 and P9. We examined sensorimotor gating (prepulse inhibition), passive avoidance, and conditioned place preference for cocaine when the animals reached adulthood. Consistent with our previous reports, we found that three days of neonatal exposure to phenobarbital significantly impaired prepulse inhibition compared with vehicle-exposed control animals. Using a step-though passive avoidance paradigm, we found that animals exposed to phenobarbital as neonates and tested as adults showed significant deficits in passive avoidance retention compared with matched controls, indicating impairment in associative memory and/or recall. Finally, we examined place preference conditioning in response to cocaine. Phenobarbital exposure did not alter the normal conditioned place preference associated with cocaine exposure. Our findings expand the profile of behavioral toxicity induced by phenobarbital. Copyright © 2014 Elsevier Inc. All rights reserved.

Effects of forest road amelioration techniques on soil bulk density, surface runoff, sediment transport, soil moisture and seedling growth

Treesearch

Randy K. Kolka; Mathew F. Smidt

2004-01-01

Although numerous methods have been used to retire roads, new technologies have evolved that can potentially ameliorate soil damage, lessen ,the generation of nonpoint source pollution and increase tree productivity on forest roads. In this study we investigated the effects of three forest road amelioration techniques, subsoiling, recontouring and traditional...

Abscisic acid ameliorates experimental IBD by downregulating cellular adhesion molecule expression and suppressing immune cell infiltration.

PubMed

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

2010-12-01

Abscisic acid (ABA) has shown effectiveness in ameliorating inflammation in obesity, diabetes and cardiovascular disease models. The objective of this study was to determine whether ABA prevents or ameliorates experimental inflammatory bowel disease (IBD). C57BL/6J mice were fed diets with or without ABA (100mg/kg) for 35 days prior to challenge with 2.5% dextran sodium sulfate (DSS). The severity of clinical disease was assessed daily. Colonic mucosal lesions were evaluated by histopathology, and cellular adhesion molecular and inflammatory markers were assayed by real-time quantitative PCR. Flow cytometry was used to quantify leukocyte populations in the blood, spleen, and mesenteric lymph nodes (MLN). The effect of ABA on cytotoxic T-lymphocyte antigen 4 (CTLA-4) expression in splenocytes was also investigated. ABA significantly ameliorated disease activity, colitis and reduced colonic leukocyte infiltration and inflammation. These improvements were associated with downregulation in vascular cell adhesion marker-1 (VCAM-1), E-selectin, and mucosal addressin adhesion marker-1 (MAdCAM-1) expression. ABA also increased CD4(+) and CD8(+) T-lymphocytes in blood and MLN and regulatory T cells in blood. In vitro, ABA increased CTLA-4 expression through a PPAR γ-dependent mechanism. We conclude that ABA ameliorates gut inflammation by modulating T cell distribution and adhesion molecule expression. Copyright © 2010 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Abscisic acid ameliorates experimental IBD by downregulating cellular adhesion molecule expression and suppressing immune cell infiltration

PubMed Central

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

2010-01-01

Background & Aims Abscisic acid (ABA) has shown effectiveness in ameliorating inflammation in obesity, diabetes and cardiovascular disease models. The objective of this study was to determine whether ABA prevents or ameliorates experimental inflammatory bowel disease (IBD). Methods C57BL/6J mice were fed diets with or without ABA (100 mg/kg) for 35 days prior to challenge with 2.5% dextran sodium sulfate (DSS). The severity of clinical disease was assessed daily. Colonic mucosal lesions were evaluated by histopathology, and cellular adhesion molecular and inflammatory markers were assayed by real-time quantitative PCR. Flow cytometry was used to quantify leukocyte populations in the blood, spleen, and mesenteric lymph nodes (MLN). The effect of ABA on cytotoxic T-lymphocyte antigen 4 (CTLA-4) expression in splenocytes was also investigated. Results ABA significantly ameliorated disease activity, colitis and reduced colonic leukocyte infiltration and inflammation. These improvements were associated with down-regulation in vascular cell adhesion marker-1 (VCAM-1), E-selectin, and mucosal addressin adhesion marker-1 (MAdCAM-1) expression. ABA also increased CD4+ and CD8+ T-lymphocytes in blood and MLN and regulatory T-cells in blood. In vitro, ABA increased CTLA-4 expression through a PPAR γ-dependent mechanism. Conclusions We conclude that ABA ameliorates gut inflammation by modulating T cell distribution and adhesion molecule expression. PMID:20236740

Indigo Naturalis ameliorates murine dextran sodium sulfate-induced colitis via aryl hydrocarbon receptor activation.

PubMed

Kawai, Shoichiro; Iijima, Hideki; Shinzaki, Shinichiro; Hiyama, Satoshi; Yamaguchi, Toshio; Araki, Manabu; Iwatani, Shuko; Shiraishi, Eri; Mukai, Akira; Inoue, Takahiro; Hayashi, Yoshito; Tsujii, Masahiko; Motooka, Daisuke; Nakamura, Shota; Iida, Tetsuya; Takehara, Tetsuo

2017-08-01

Indigo Naturalis (IN) is used as a traditional herbal medicine for ulcerative colitis (UC). However, the mechanisms of action of IN have not been clarified. We aimed to evaluate the efficacy of IN for ameliorating colonic inflammation. We further investigated the mechanisms of action of IN. Colitis severity was assessed in dextran sodium sulfate-induced colitis and trinitrobenzene sulfonic acid-induced colitis models with or without the oral administration of IN or indigo, which is a known major component of IN. Colonic lamina propria (LP) mononuclear cells isolated from IN-treated mice were analyzed with quantitative reverse transcription polymerase chain reaction (qRT-PCR) and flow cytometry. LP and splenic mononuclear cells cultured in vitro with IN or indigo were also analyzed. The role of the candidate receptor for indigo, the aryl hydrocarbon receptor (AhR), was analyzed using Ahr-deficient mice. Colitis severity was significantly ameliorated in the IN and indigo treatment groups compared with the control group. The mRNA expression levels of interleukin (Il)-10 and Il-22 in the LP lymphocytes were increased by IN treatment. The treatment of splenocytes with IN or indigo increased the expression of anti-inflammatory cytokines and resulted in the expansion of IL-10-producing CD4 + T cells and IL-22-producing CD3 - RORγt + cells, but not CD4 + Foxp3 + regulatory T cells. The amelioration of colitis by IN or indigo was abrogated in Ahr-deficient mice, in association with diminished regulatory cytokine production. IN and indigo ameliorated murine colitis through AhR signaling activation, suggesting that AhR could be a promising therapeutic target for UC.

Poly(ADP-ribose) polymerase inhibition combined with irradiation: A dual treatment concept to prevent neointimal hyperplasia after endarterectomy

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

Beller, Carsten J.; Kosse, Jens; Radovits, Tamas

2006-11-01

Purpose: In a rat model of endarterectomy we investigated the potential role of the peroxynitrite-poly(ADP-ribose) polymerase (PARP) pathway in neointima formation and the effects of irradiation, pharmacologic inhibition of PARP, or combined pharmacologic inhibition of PARP and irradiation on vascular remodeling. Methods and Materials: Carotid endarterectomy was performed by incision of the left carotid artery with removal of intima in Sprague-Dawley rats. Six groups were studied: sham-operated rats (n = 10), control endarterectomized rats (n = 10), or endarterectomized rats irradiated with 15 Gy (n = 10), or treated with PARP inhibitor, INO-1001 (5 mg/kg/day) (n = 10), or withmore » combined treatment with INO-1001 and irradiation with 5 Gy (n = 10) or with 15 Gy (n = 10). After 21 days, neointima formation and vascular remodeling were assessed. Results: Neointima formation after endarterectomy was inhibited by postoperative irradiation with 15 Gy and was attenuated by PARP inhibition. However, in parallel to inhibition of neointimal hyperplasia, activation of the peroxynitrite-PARP pathway in the outer vessel wall layers was triggered by postoperative irradiation. Combined pharmacologic PARP inhibition and irradiation with 15 Gy significantly reduced both neointimal hyperplasia and activation of the peroxynitrite-PARP pathway in the outer vessel wall layers. Combination of PARP inhibition and irradiation with 5 Gy was less effective than both PARP inhibition or irradiation with 15 Gy alone. Conclusions: We conclude, that combined PARP inhibition and irradiation with 15 Gy may be a new dual strategy for prevention of restenosis after surgical vessel reconstruction: combining the strong antiproliferative effect of irradiation and ameliorating irradiation-induced side effects caused by excessive PARP activation.« less

A crucial role of ROCK for alleviation of senescence-associated phenotype.

PubMed

Park, Joon Tae; Kang, Hyun Tae; Park, Chi Hyun; Lee, Young-Sam; Cho, Kyung A; Park, Sang Chul

2018-06-01

In our previous study, we uncovered a novel mechanism in which amelioration of Hutchinson-Gilford progeria syndrome (HGPS) phenotype is mediated by mitochondrial functional recovery upon rho-associated protein kinase (ROCK) inhibition. However, it remains elusive whether this mechanism is also applied to the amelioration of normal aging cells. In this study, we used Y-27632 and fasudil as effective ROCK inhibitors, and examined their role in senescence. We found that ROCK inhibition induced the functional recovery of the mitochondria as well as the metabolic reprogramming, which are two salient features that are altered in normal aging cells. Moreover, microarray analysis revealed that the up-regulated pathway upon ROCK inhibition is enriched for chromatin remodeling genes, which may play an important role in the alleviation of senescence-associated cell cycle arrest. Indeed, ROCK inhibition induced cellular proliferation, concomitant with the amelioration of senescent phenotype. Furthermore, the restorative effect by ROCK inhibition was observed in vivo as evidenced by the facilitated cutaneous wound healing. Taken together, our data indicate that ROCK inhibition might be utilized to ameliorate normal aging process and to treat age-related disease. Copyright © 2018 Elsevier Inc. All rights reserved.

Perfluorooctanoic acid exposure induces endoplasmic reticulum stress in the liver and its effects are ameliorated by 4-phenylbutyrate.

PubMed

Yan, Shengmin; Zhang, Hongxia; Wang, Jianshe; Zheng, Fei; Dai, Jiayin

2015-10-01

Perfluoroalkyl acids (PFAAs) are a group of widely used anthropogenic compounds. As one of the most dominant PFAAs, perfluorooctanoic acid (PFOA) has been suggested to induce hepatotoxicity and several other toxicological effects. However, details on the mechanisms for PFOA-induced hepatotoxicity still need to be elucidated. In this study, we observed the occurrence of endoplasmic reticulum (ER) stress in mouse livers and HepG2 cells after PFOA exposure using several familiar markers for the unfolded protein response (UPR). ER stress in HepG2 cells after PFOA exposure was not significantly influenced by autophagy inhibition or stimulation. The antioxidant defense system was significantly disturbed in mouse livers after PFOA exposure, and reactive oxygen species (ROS) were increased in cells exposed to PFOA for 24 h. However, N-acetyl-L-cysteine (NAC) pretreatment did not satisfactorily alleviate the UPR in cells exposed to PFOA even though the increase of ROS was less evident. Furthermore, exposure of HepG2 cells to PFOA in the presence of sodium 4-phenylbutyrate (4-PBA), a chemical chaperone and ER stress inhibitor, suggested that 4-PBA alleviated the UPR and autophagosome accumulation induced by PFOA in cells. In addition, several toxicological effects attributed to PFOA exposure, including cell cycle arrest, proteolytic activity impairment, and neutral lipid accumulation, were also improved by 4-PBA cotreatment in cells. In vivo study demonstrated that PFOA-induced lipid metabolism perturbation and liver injury were partially ameliorated by 4-PBA in mice after 28 days of exposure. These findings demonstrated that PFOA-induced ER stress leading to UPR might play an important role in PFOA-induced hepatotoxic effects, and chemical chaperone 4-PBA could ameliorate the effects. Copyright © 2015. Published by Elsevier Inc.

Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity.

PubMed

Chen, Zhongyi; Guo, Lilu; Zhang, Yongqin; Walzem, Rosemary L; Pendergast, Julie S; Printz, Richard L; Morris, Lindsey C; Matafonova, Elena; Stien, Xavier; Kang, Li; Coulon, Denis; McGuinness, Owen P; Niswender, Kevin D; Davies, Sean S

2014-08-01

Metabolic disorders, including obesity, diabetes, and cardiovascular disease, are widespread in Westernized nations. Gut microbiota composition is a contributing factor to the susceptibility of an individual to the development of these disorders; therefore, altering a person's microbiota may ameliorate disease. One potential microbiome-altering strategy is the incorporation of modified bacteria that express therapeutic factors into the gut microbiota. For example, N-acylphosphatidylethanolamines (NAPEs) are precursors to the N-acylethanolamide (NAE) family of lipids, which are synthesized in the small intestine in response to feeding and reduce food intake and obesity. Here, we demonstrated that administration of engineered NAPE-expressing E. coli Nissle 1917 bacteria in drinking water for 8 weeks reduced the levels of obesity in mice fed a high-fat diet. Mice that received modified bacteria had dramatically lower food intake, adiposity, insulin resistance, and hepatosteatosis compared with mice receiving standard water or control bacteria. The protective effects conferred by NAPE-expressing bacteria persisted for at least 4 weeks after their removal from the drinking water. Moreover, administration of NAPE-expressing bacteria to TallyHo mice, a polygenic mouse model of obesity, inhibited weight gain. Our results demonstrate that incorporation of appropriately modified bacteria into the gut microbiota has potential as an effective strategy to inhibit the development of metabolic disorders.

Ameliorative effects of amide derivatives of 1,3,4-thiadiazoles on scopolamine induced cognitive dysfunction.

PubMed

Kulshreshtha, Akanksha; Piplani, Poonam

2016-10-21

The present study reports the effect of amide derivatives of 1,3,4-thiadizoles on scopolamine induced deficit cholinergic neurotransmission and oxidative stress serving as promising leads for the therapeutics of cognitive dysfunction. Fourteen compounds (2c-8d) have been synthesised and evaluated against behavioural alterations using step down passive avoidance protocol and morris water maze and at a dose of 0.5 mg/kg with reference to the standard, Rivastigmine. All the synthesised compounds were evaluated for their in vitro acetylcholinesterase (AChE) inhibition at five different concentrations using mice brain homogenate as the source of the enzyme. Biochemical estimation of markers of oxidative stress (lipid peroxidation, superoxide dismutase, glutathione, plasma nitrite, catalase) has also been carried out to assess the role of synthesised molecules on the oxidative damage induced by scopolamine. The compounds 5c, 6c and 8c displayed appreciable activity with an IC50 value of 3 μM, 3.033 μM and 2.743 μM, respectively towards acetylcholinesterase inhibition. These compounds also decreased scopolamine induced oxidative stress, thus serving as promising leads for the amelioration of oxidative stress induced cognitive decline. The molecular docking study performed to predict the binding mode of the compounds also suggested that these compounds bind appreciably with the amino acids present in the active site of recombinant human acetylcholinesterase (rhAChE). The results indicated that these compounds could be further traversed as inhibitors of AChE and oxidative stress for the treatment of cognitive dysfunction. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Aminoguanidine inhibits albuminuria, but not the formation of advanced glycation end-products in skin collagen of diabetic rats.

PubMed

Degenhardt, T P; Fu, M X; Voss, E; Reiff, K; Neidlein, R; Strein, K; Thorpe, S R; Baynes, J W; Reiter, R

1999-02-01

Aminoguanidine, an inhibitor of advanced glycation reactions in vitro, inhibits the development of diabetic complications in animal models of diabetes, suggesting that it acts by inhibition of advanced glycation reactions in vivo. However, effects of aminoguanidine on the formation of specific advanced glycation end-products (AGEs) in vivo have not been rigorously examined. Therefore, we studied the effects of aminoguanidine on the formation of pentosidine and N(epsilon)-(carboxymethyl)lysine (CML), measured by analytical chemical methods, in collagen of streptozotocin-diabetic Lewis rats at doses which ameliorated urinary albumin excretion, an index of diabetic nephropathy. At 12 weeks, diabetic animals had fivefold higher blood glucose, threefold higher glycated hemoglobin and fivefold higher collagen glycation, compared to metabolically healthy controls; pentosidine and CML in skin collagen were increased by approximately 30 and 150%, respectively. Administration of aminoguanidine, 50 mg/kg by daily intraperitoneal injection, significantly inhibited the development of albuminuria (approximately 60%, P < 0.01) in diabetic rats, without an effect on blood glucose or glycation of hemoglobin or collagen. Surprisingly, aminoguanidine failed to inhibit the increase in pentosidine and CML in diabetic rat skin collagen. Similar results were obtained in an independent experiment in which aminoguanidine was administered in drinking water at a dose of 0.5 g/l. We conclude that the therapeutic benefits of aminoguanidine on albuminuria may not be the result of inhibition of AGE formation.

Apple flavonoid phloretin inhibits Escherichia coli O157:H7 biofilm formation and ameliorates colon inflammation in rats.

PubMed

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

2011-12-01

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 stx(2)), 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.

Blockade of store-operated calcium entry alleviates ethanol-induced hepatotoxicity via inhibiting apoptosis

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

Cui, Ruibing; Yan, Lihui; Luo, Zheng

2015-08-15

Extracellular Ca{sup 2+} influx has been suggested to play a role in ethanol-induced hepatocyte apoptosis and necrosis. Previous studies indicated that store-operated Ca{sup 2+} entry (SOCE) was involved in liver injury induced by ethanol in HepG2 cells. However, the mechanisms underlying liver injury caused by SOCE remain unclear. We aimed to investigate the effects and mechanism of SOCE inhibition on liver injury induced by ethanol in BRL cells and Sprague–Dawley rats. Our data demonstrated that ethanol (0–400 mM) dose-dependently increased hepatocyte injury and 100 mM ethanol significantly upregulated the mRNA and protein expression of SOC for at least 72 hmore » in BRL cells. Blockade of SOCE by pharmacological inhibitors and sh-RNA knockdown of STIM1 and Orai1 attenuated intracellular Ca{sup 2+} overload, restored the mitochondrial membrane potential (MMP), decreased cytochrome C release and inhibited ethanol-induced apoptosis. STIM1 and Orai1 expression was greater in ethanol-treated than control rats, and the SOCE inhibitor corosolic acid ameliorated the histopathological findings and alanine transaminase and aspartate transaminase activity as well as decreased cytochrome C release and inhibited alcohol-induced cell apoptosis. These findings suggest that SOCE blockade could alleviate alcohol-induced hepatotoxicity via inhibiting apoptosis. SOCE might be a useful therapeutic target in alcoholic liver diseases. - Highlights: • Blockade of SOCE alleviated overload of Ca{sup 2+} and hepatotoxicity after ethanol application. • Blockade of SOCE inhibited mitochondrial apoptosis after ethanol application. • SOCE might be a useful therapeutic target in alcoholic liver diseases.« less

HDAC Inhibition Improves the Sarcoendoplasmic Reticulum Ca2+-ATPase Activity in Cardiac Myocytes

PubMed Central

Meraviglia, Viviana; Sacchetto, Roberta; Motta, Benedetta M.; Corti, Corrado; D’Elia, Yuri; Rosato-Siri, Marcelo D.; Suffredini, Silvia; Pompilio, Giulio; Pramstaller, Peter P.; Stilli, Donatella

2018-01-01

SERCA2a is the Ca2+ ATPase playing the major contribution in cardiomyocyte (CM) calcium removal. Its activity can be regulated by both modulatory proteins and several post-translational modifications. The aim of the present work was to investigate whether the function of SERCA2 can be modulated by treating CMs with the histone deacetylase (HDAC) inhibitor suberanilohydroxamic acid (SAHA). The incubation with SAHA (2.5 µM, 90 min) of CMs isolated from rat adult hearts resulted in an increase of SERCA2 acetylation level and improved ATPase activity. This was associated with a significant improvement of calcium transient recovery time and cell contractility. Previous reports have identified K464 as an acetylation site in human SERCA2. Mutants were generated where K464 was substituted with glutamine (Q) or arginine (R), mimicking constitutive acetylation or deacetylation, respectively. The K464Q mutation ameliorated ATPase activity and calcium transient recovery time, thus indicating that constitutive K464 acetylation has a positive impact on human SERCA2a (hSERCA2a) function. In conclusion, SAHA induced deacetylation inhibition had a positive impact on CM calcium handling, that, at least in part, was due to improved SERCA2 activity. This observation can provide the basis for the development of novel pharmacological approaches to ameliorate SERCA2 efficiency. PMID:29385061

HDAC Inhibition Improves the Sarcoendoplasmic Reticulum Ca2+-ATPase Activity in Cardiac Myocytes.

PubMed

Meraviglia, Viviana; Bocchi, Leonardo; Sacchetto, Roberta; Florio, Maria Cristina; Motta, Benedetta M; Corti, Corrado; Weichenberger, Christian X; Savi, Monia; D'Elia, Yuri; Rosato-Siri, Marcelo D; Suffredini, Silvia; Piubelli, Chiara; Pompilio, Giulio; Pramstaller, Peter P; Domingues, Francisco S; Stilli, Donatella; Rossini, Alessandra

2018-01-31

SERCA2a is the Ca 2+ ATPase playing the major contribution in cardiomyocyte (CM) calcium removal. Its activity can be regulated by both modulatory proteins and several post-translational modifications. The aim of the present work was to investigate whether the function of SERCA2 can be modulated by treating CMs with the histone deacetylase (HDAC) inhibitor suberanilohydroxamic acid (SAHA). The incubation with SAHA (2.5 µM, 90 min) of CMs isolated from rat adult hearts resulted in an increase of SERCA2 acetylation level and improved ATPase activity. This was associated with a significant improvement of calcium transient recovery time and cell contractility. Previous reports have identified K464 as an acetylation site in human SERCA2. Mutants were generated where K464 was substituted with glutamine (Q) or arginine (R), mimicking constitutive acetylation or deacetylation, respectively. The K464Q mutation ameliorated ATPase activity and calcium transient recovery time, thus indicating that constitutive K464 acetylation has a positive impact on human SERCA2a (hSERCA2a) function. In conclusion, SAHA induced deacetylation inhibition had a positive impact on CM calcium handling, that, at least in part, was due to improved SERCA2 activity. This observation can provide the basis for the development of novel pharmacological approaches to ameliorate SERCA2 efficiency.

The amelioration effect of tranexamic acid in wrinkles induced by skin dryness.

PubMed

Hiramoto, Keiichi; Sugiyama, Daijiro; Takahashi, Yumi; Mafune, Eiichi

2016-05-01

Tranexamic acid (trans-4-aminomethylcyclohexanecarboxylic acid) is a medical amino acid widely used as an anti-inflammatory and a whitening agent. This study examined the effect of tranexamic acid administration in wrinkle formation following skin dryness. We administered tranexamic acid (750mg/kg/day) orally for 20 consecutive days to Naruto Research Institute Otsuka Atrichia (NOA) mice, which naturally develop skin dryness. In these NOA mice, deterioration of transepidermal water loss (TEWL), generation of wrinkles, decrease of collagen type I, and increases in mast cell proliferation and tryptase and matrix metalloproteinase (MMP-1) release were observed. However, these symptoms were improved by tranexamic acid treatment. Moreover, the increase in the β-endorphin level in the blood and the expression of μ-opioid receptor on the surface of fibroblasts increased by tranexamic acid treatment. In addition, when the fibroblasts induced by tranexamic acid treatment were removed, the amelioration effect by tranexamic acid treatment was halved. On the other hand, tranexamic acid treated NOA mice and mast cell removal in tranexamic acid treated NOA mice did not result in changes in the wrinkle amelioration effect. Additionally, the amelioration effect of mast cell deficient NOA mice was half that of tranexamic acid treated NOA mice. These results indicate that tranexamic acid decreased the proliferation of mast cells and increases the proliferation of fibroblasts, subsequently improving wrinkles caused by skin dryness. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Haematolohical profile of subacute oral toxicity of molybdenum and ameliorative efficacy of copper salt in goats.

PubMed

Kusum; Raina, R; Verma, P K; Pankaj, N K; Kant, V; Kumar, J; Srivastava, A K

2010-07-01

Molybdenum toxicity produces a state of secondary hypocuprosis, resulting into alterations in normal hematological profile. In the present study, ammonium molybdate alone and with copper sulfate (II) pentahydrate (ameliorative agent) was administered orally for 30 consecutive days in healthy goats of group 1 and 2, respectively, to access the effect on the hematological profile on different predetermined days of dosing. Administration of ammonium molybdate alone produced significant decline in the mean values of hemoglobin (Hb), packed cell volume (PCV), total leukocyte count (TLC), total erythrocyte count (TEC), and mean corpuscular hemoglobin concentration (MCHC), with a significant increase in neutrophil level and mean corpuscular volume (MCV). However, values of erythrocyte sedimentation rate, mean corpuscular hemoglobin, and differential leukocyte count were not significantly altered. On comparing observations of ameliorative group with the group 1 goats, it is concluded that the ameliorative copper salt has beneficial effects in alleviating the alterations in the values of Hb, PCV, TLC, TEC, MCV, MCHC, and neutrophils.

Haematolohical Profile of Subacute Oral Toxicity of Molybdenum and Ameliorative Efficacy of Copper Salt in Goats

PubMed Central

Kusum; Raina, R.; Verma, P. K.; Pankaj, N. K.; Kant, V.; Kumar, J.; Srivastava, A. K.

2010-01-01

Molybdenum toxicity produces a state of secondary hypocuprosis, resulting into alterations in normal hematological profile. In the present study, ammonium molybdate alone and with copper sulfate (II) pentahydrate (ameliorative agent) was administered orally for 30 consecutive days in healthy goats of group 1 and 2, respectively, to access the effect on the hematological profile on different predetermined days of dosing. Administration of ammonium molybdate alone produced significant decline in the mean values of hemoglobin (Hb), packed cell volume (PCV), total leukocyte count (TLC), total erythrocyte count (TEC), and mean corpuscular hemoglobin concentration (MCHC), with a significant increase in neutrophil level and mean corpuscular volume (MCV). However, values of erythrocyte sedimentation rate, mean corpuscular hemoglobin, and differential leukocyte count were not significantly altered. On comparing observations of ameliorative group with the group 1 goats, it is concluded that the ameliorative copper salt has beneficial effects in alleviating the alterations in the values of Hb, PCV, TLC, TEC, MCV, MCHC, and neutrophils. PMID:21170251

Cyanidin-3-O-glucoside ameliorates diabetic nephropathy through regulation of glutathione pool.

PubMed

Qin, Yan; Zhai, Qianqian; Li, Yan; Cao, Meng; Xu, Yun; Zhao, Kelei; Wang, Tao

2018-07-01

Diabetic nephropathy (DN) is a common complication of diabetes and the major cause of chronic kidney disease. Cyanidin 3-glucoside (C3G) is the most widespread anthocyanin in nature. In the present study, we aimed to investigate the possible effects of C3G on DN in db/db mice. We found that body weights and high levels of fasting blood glucose, serum insulin, C-peptide, glycosylated hemoglobin A1c, and systolic blood pressure in diabetic mice were significantly reduced by C3G. C3G also reduced the ratio of kidney to body weight and the levels of blood urea nitrogen (BUN), serum creatinine, urinary albumin content and albumin/creatinine ratio (ACR), ameliorated the pathological changes of kidneys, reduced the surface area of Bowman's capsule, glomerular tuft, Bowman's space, and decreased renal expression of collagen IV, fibronectin, transforming growth factor β 1 (TGFβ1), matrix metalloprotein 9 (MMP9) and α-smooth muscle actin (α-SMA) in db/db mice. The Lee's index, perirenal white adipose tissue weight, and high levels of blood and renal triglyceride and cholesterol were decreased by C3G. Moreover, C3G reduced systemic levels and renal expression of tumor necrosis factor ɑ (TNFɑ), IL-1ɑ, and monocyte chemotactic protein-1 (MCP-1), indicating the inhibition of inflammation. Furthermore, C3G increased glutathione (GSH) level and decreased GSSG level in kidneys of diabetic mice. The renal mRNA expression of glutamate-cysteine ligase catalytic subunit (GCLC) and glutamate-cysteine ligase modifier subunit (GCLM) was increased by C3G in diabetic mice. Buthionine sulphoximine (BSO), an inhibitor of GSH synthesis, inhibited the effects of C3G on glucose metabolic dysfunction and DN. The data demonstrates that enhancement of GSH pool is involved in the renal-protective effects of C3G. Overall, C3G could be a promising therapeutic option for attenuation of diabetes and DN. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Pirfenidone ameliorates lipopolysaccharide-induced pulmonary inflammation and fibrosis by blocking NLRP3 inflammasome activation.

PubMed

Li, Yi; Li, Haitao; Liu, Shuai; Pan, Pinhua; Su, Xiaoli; Tan, Hongyi; Wu, Dongdong; Zhang, Lemeng; Song, Chao; Dai, Minhui; Li, Qian; Mao, Zhi; Long, Yuan; Hu, Yongbin; Hu, Chengping

2018-05-18

Acute respiratory distress syndrome(ARDS)is a severe clinical disorder characterized by its acute onset, diffuse alveolar damage, intractable hypoxemia, and non-cardiogenic pulmonary edema. Acute lung injury(ALI) can trigger persistent lung inflammation and fibrosis through activation of the NLRP3 inflammasome and subsequent secretion of mature IL-1β, suggesting that the NLRP3 inflammasome is a potential therapeutic target for ALI, for which new therapeutic approaches are needed. Our present study aims to assess whether pirfenidone,with anti-fibrotic and anti-inflammatory properties, can improve LPS-induced inflammation and fibrosis by inhibiting NLRP3 inflammasome activation. Male C57BL/6 J mice were intratracheally injected with LPS to induce ALI. Mice were administered pirfenidone by oral gavage throughout the entire experimental course. The mouse macrophage cell line (J774 A.1) was incubated with LPS and ATP, with or without PFD pre-treatment. We demonstrated that PFD remarkably ameliorated LPS-induced pulmonary inflammation and fibrosis and reduced IL-1β and TGF-β1 levels in bronchoalveolar lavage fluid(BALF). Pirfenidone substantially reduced NLRP3 and ASC expression and inhibited caspase-1 activation and IL-1β maturation in lung tissues. In vitro, the experiments revealed that PFD significantly suppressed LPS/ATP-induced production of reactive oxygen species (ROS) and decreased caspase-1 activation and the level of IL-1β in J774 A.1 cells. Taken together, the administration of PFD reduced LPS-induced lung inflammation and fibrosis by blocking NLRP3 inflammasome activation and subsequent IL-1β secretion. These findings indicated that PFD can down-regulate NLRP3 inflammasome activation and that it may offer a promising therapeutic approach for ARDS patients. Copyright © 2018 Elsevier Ltd. All rights reserved.

Adenosine 5'-monophosphate ameliorates D-galactosamine/lipopolysaccharide-induced liver injury through an adenosine receptor-independent mechanism in mice.

PubMed

Zhan, Y; Wang, Z; Yang, P; Wang, T; Xia, L; Zhou, M; Wang, Y; Wang, S; Hua, Z; Zhang, J

2014-01-09

D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced lethality and acute liver failure is dependent on endogenously produced inflammatory cytokines. Adenosine has been proven to be a central role in the regulation of inflammatory response. It is not entirely clear that which adenosine action is actually crucial to limiting inflammatory tissue destruction. Here we showed that GalN/LPS challenge elevated hepatic adenosine and induced lethality in adenosine receptor-deficient mice with equal efficiency as wild-type mice. In GalN/LPS-treated mice, pretreatment with adenosine 5'-monophosphate (5'-AMP) significantly elevated hepatic adenosine level and reduced mortality through decreasing cytokine and chemokine production. In RAW264.7 cells, 5'-AMP treatment inhibited the production of inflammatory cytokines, which is not mediated through adenosine receptors. 5'-AMP failed to attenuate LPS-induced nuclear factor-κB (NF-κB) p65 nuclear translocation, but reduced LPS-induced recruitment of NF-κB p65 to inflammatory gene promoters and decreased LPS-induced enrichment of H3K4 dimethylation at the tumor necrosis factor-α (TNF-α) promoter, which was involved in 5'-AMP-induced elevation of cellular adenosine and a decline of methylation potential. In vitro biochemical analysis revealed that adenosine directly attenuated recruitment of NF-κB to the TNF-α and interleukin-6 promoters. Our findings demonstrate that 5'-AMP-inhibiting inflammatory response is not mediated by adenosine receptors and it may represent a potential protective agent for amelioration of LPS-induced liver injury.

Intestinal ameliorative effects of traditional Ogi-tutu, Vernonia amygdalina and Psidium guajava in mice infected with Vibrio cholera.

PubMed

Shittu, Olufunke B; Ajayi, Olusola L; Bankole, Samuel O; Popoola, Temitope Os

2016-06-01

Cholera, a severe acute watery diarrhea caused by Vibrio cholerae is endemic in Nigeria with most cases occurring in the rural areas. In South West Nigeria, some individuals resort to alternative treatments such as Ogi-tutu, Psidium guajava and Vernonia amygdalina during infections. The effectiveness of these alternatives in the prevention and treatment of V. cholerae infection requires experimental investigation. This study was designed to investigate the ameliorative effects of Ogi-tutu, Vernonia amygdalina and Psidium guajava on intestinal histopathology of experimental mice infected with V. cholerae. Preliminary investigation of in vitro vibriocidal activities of these alternatives were carried out using agar cup diffusion assay. For ameliorative effects, adult mice were inoculated with 100 µl (106 cells) of Vibrio cholerae and dosed at 0 h (immediate prevention) and 4 h (treatment of infection) and their intestines were histopathologically evaluated. The histopathological changes were the same irrespective of the treated groups, but the lesions varied in extent and severity. The ameliorative effects in decreasing order were V. amygdalina > P. guajava > Ogi-tutu. V. amygdalina gave the best ameliorative effects in the prevention and treatment of V. cholerae infection.

The HDAC Inhibitor TSA Ameliorates a Zebrafish Model of Duchenne Muscular Dystrophy.

PubMed

Johnson, Nathan M; Farr, Gist H; Maves, Lisa

2013-09-17

Zebrafish are an excellent model for Duchenne muscular dystrophy. In particular, zebrafish provide a system for rapid, easy, and low-cost screening of small molecules that can ameliorate muscle damage in dystrophic larvae. Here we identify an optimal anti-sense morpholino cocktail that robustly knocks down zebrafish Dystrophin (dmd-MO). We use two approaches, muscle birefringence and muscle actin expression, to quantify muscle damage and show that the dmd-MO dystrophic phenotype closely resembles the zebrafish dmd mutant phenotype. We then show that the histone deacetylase (HDAC) inhibitor TSA, which has been shown to ameliorate the mdx mouse Duchenne model, can rescue muscle fiber damage in both dmd-MO and dmd mutant larvae. Our study identifies optimal morpholino and phenotypic scoring approaches for dystrophic zebrafish, further enhancing the zebrafish dmd model for rapid and cost-effective small molecule screening.