IL-33 Downregulates Hepatic Carboxylesterase 1 in Acute Liver Injury via Macrophage-derived Exosomal miR-27b-3p.

Background and Aims: We previously reported that carboxylesterase 1 (CES1) expression was suppressed following liver injury. The study aimed to explore the role of interleukin (IL)-33 in liver injury and examine the mechanism by which IL-33 regulates CES1. Methods: IL-33 and CES1 levels were determined in the livers of patients and lipopolysaccharide (LPS)-, acetaminophen (APAP)-treated mice. We constructed IL-33 and ST2 knockout (KO) mice. ST2-enriched immune cells in livers were screened to identify the responsible cells. Macrophage-derived exosome (MDE) activity was tested by adding exosome inhibitors. Micro-RNAs (miRs) were extracted from control and IL-33-stimulated MDEs (IL-33-MDEs) and subjected miR sequencing (miR-Seq). Candidate miR was tested in vitro and in vivo and its binding of a target gene was assessed by luciferase reporter assays. Lentivirus-vector cellular transfection and transcript silencing were used to examine pathways mediating IL-33 suppression of miR-27b-3p. Results: Patient liver IL-33 and CES1 expression levels were inversely correlated. CES1 downregulation in liver injury was rescued in both IL-33-deficient and ST2 KO mice. Macrophages were shown to be responsible for IL-33 effects. IL-33-MDEs reduced CES1 levels in hepatocytes. Exosomal miR-Seq and qRT-PCR demonstrated increased miR-27b-3p levels in IL-33-MDEs; miR-27b-3p was implicated in Nrf2 targeting. IL-33 inhibition of miR-27b-3p was found to be GATA3-dependent. Conclusions: IL-33-ST2-GATA3 pathway signaling increases miR-27b-3p content in MDEs, which upon being internalized by hepatocytes reduce CES1 expression by inhibiting Nrf2. The elucidation of this mechanism in this study contributes to a better understanding of CES1 dysregulation in liver injury.

N-acetylcysteine facilitates extinction of cued fear memory in rats via reestablishing basolateral amygdala glutathione homeostasis.

Individual differences in the development of uncontrollable fear in response to traumatic stressors have been observed in clinic, but the underlying mechanisms remain unknown. In the present study we first conducted a meta-analysis of published clinical data and found that malondialdehyde, an oxidative stress biomarker, was significantly elevated in the blood of patients with fear-related anxiety disorders. We then carried out experimental study in rats subjected to fear conditioning. We showed that reestablishing redox homeostasis in basolateral amygdale (BLA) after exposure to fear stressors determined the capacity of learned fear inhibition. Intra-BLA infusion of buthionine sulfoximine (BSO) to deplete the most important endogenous antioxidant glutathione (GSH) blocked fear extinction, whereas intra-BLA infusion of dithiothreitol or N-acetylcysteine (a precursor of GSH) facilitated extinction. In electrophysiological studies conducted on transverse slices, we showed that fear stressors induced redox-dependent inhibition of NMDAR-mediated synaptic function, which was rescued by extinction learning or reducing agents. Our results reveal a novel pharmacological strategy for reversing impaired fear inhibition and highlight the role of GSH in the treatment of psychiatric disorders.

[Retracted] microRNA­206 overexpression inhibits cellular proliferation and invasion of estrogen receptor α­positive ovarian cancer cells.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the western blotting data shown in Fig. 1A and Transwell cell migration data shown in Fig. 4A were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive any reply. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 9: 1703­1708, 2014; DOI: 10.3892/mmr.2014.2021].

Vitexin attenuates epithelial ovarian cancer cell viability and motility in vitro and carcinogenesis in vivo via p38 and ERK1/2 pathways related VEGFA.

BACKGROUND: Epithelial ovarian cancer (EOC) is the most common type of ovarian tumor, however, effective treatment does not currently exist for this condition. This study evaluated the role of vitexin in mitigating EOC both in vitro and in vivo. METHOD: SKOV-3 cells were used for in vitro experimentation. Xenotransplantation mouse models were set up by subcutaneously injecting mice with SKOV-3 cells. CCK8 was used to screen the optimal dose in vitro. Cell proliferation, invasion, number of microtubule nodules and apoptosis were respectively detected by colony formation assay, transwell assay, microtubule formation assay and flow cytometry. TUNEL and immunohistochemistry were used to detect tissues apoptosis and VEGF content. Western blot assay was used to detect the expression of Ki67, caspase-3, VEGFA, VEGFR2, ERK1/2 and p38. RESULTS: In vitro experiment, compared with the control group, 10 µL of vitexin significantly reduced Ki67 levels and enhanced tumor cell apoptosis rate. Additionally, the colony forming rate, invasive cells per field, and number of nodes/HPF in vitexin treated group decreased dramatically. The result of western blot showed that levels of p-p38/p38 and p-ERK1/2/ERK1/2 also noticeably decreased. In vivo experiment, 40 mg/kg of vitexin significantly inhibited tumor growth. In addition, vitexin significantly enhanced the percentage of tissues apoptosis, which was accompanied by a decrease in the percentage of VEGF-positive cells. CONCLUSIONS: Vitexin decreased the proliferation and invasion of SKOV-3 cells and noticeably reduced tumor growth. These findings suggest that vitexin could be a promising therapy for EOC.

S-methyl-L-cysteine Protects against Antimycin A-induced Mitochondrial Dysfunction in Neural Cells via Mimicking Endogenous Methionine-centered Redox Cycle.

Mitochondrial superoxide overproduction is believed to be responsible for the neurotoxicity associated with neurodegeneration. Mitochondria-targeted antioxidants, such as MitoQ, have emerged as potentially effective antioxidant therapies. Methionine sulfoxide reductase A (MsrA) is a key mitochondrial-localized endogenous antioxidative enzyme and it can scavenge oxidizing species by catalyzing the methionine (Met)-centered redox cycle (MCRC). In this study, we observed that the natural L-Met acted as a good scavenger for antimycin A-induced mitochondrial superoxide overproduction in PC12 cells. This antioxidation was largely dependent on the Met oxidase activity of MsrA. S-methyl-L-cysteine (SMLC), a natural analogue of Met that is abundantly found in garlic and cabbage, could activate the Met oxidase activity of MsrA to scavenge free radicals. Furthermore, SMLC protected against antimycin A-induced mitochondrial membrane depolarization and alleviated 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity. Thus, our data highlighted the possibility for SMLC supplement in the detoxication of mitochondrial damage by activating the Met oxidase activity of MsrA.

MsrA Suppresses Inflammatory Activation of Microglia and Oxidative Stress to Prevent Demyelination via Inhibition of the NOX2-MAPKs/NF-κB Signaling Pathway.

INTRODUCTION: Demyelination causes neurological deficits involving visual, motor, sensory symptoms. Deregulation of several enzymes has been identified in demyelination, which holds potential for the development of treatment strategies for demyelination. However, the specific effect of methionine sulfoxide reductase A (MsrA) on demyelination remains unclear. Hence, this study aims to explore the effect of MsrA on oxidative stress and inflammatory response of microglia in demyelination. METHODS: Initially, we established a mouse model with demyelination induced by cuprizone and a cell model provoked by lipopolysaccharide (LPS). The expression of MsrA in wild-type (WT) and MsrA-knockout (MsrA-/-) mice were determined by RT-qPCR and Western blot analysis. In order to further explore the function of MsrA on inflammatory response, and oxidative stress in demyelination, we detected the expression of microglia marker Iba1, inflammatory factors TNF-α and IL-1ß and intracellular reactive oxygen species (ROS), superoxide dismutase (SOD) activity, as well as expression of the NOX2-MAPKs/NF-κB signaling pathway-related genes in MsrA-/- mice and LPS-induced microglia following different treatments. RESULTS: MsrA expression was downregulated in MsrA-/- mice. MsrA silencing was shown to produce severely injured motor coordination, increased expressions of Iba1, TNF-α, IL-1ß, ROS and NOX2, and extent of ERK, p38, IκBα, and p65 phosphorylation, but reduced SOD activity. Conjointly, our study suggests that Tat-MsrA fusion protein can prevent the cellular inflammatory response and subsequent demyelination through negative regulation of the NOX2-MAPKs/NF-κB signaling pathway. CONCLUSION: Our data provide a profound insight on the role of endogenous antioxidative defense systems such as MsrA in controlling microglial function.

Astragaloside IV Alleviates Tacrolimus-Induced Chronic Nephrotoxicity via p62-Keap1-Nrf2 Pathway.

Tacrolimus-induced chronic nephrotoxicity (TIN) hinders its long-term use in patients. However, there are no drugs available in the clinic to relieve it at present. Astragaloside IV (AS-IV) is a saponin extract of the Astragalus which is widely used in the treatment of kidney disease. This study aimed to investigate the effect of AS-IV on TIN and its underlying mechanism. Herein, C57BL/6 mice were treated with tacrolimus and/or AS-IV for 4 weeks, and then the renal function, fibrosis, oxidative stress and p62-Keap1-Nrf2 pathway were evaluated to ascertain the contribution of AS-IV and p62-Keap1-Nrf2 pathway to TIN. Our results demonstrated that AS-IV significantly improved renal function and alleviated tubulointerstitial fibrosis compared with the model group. The expression of fibrosis-related proteins, including TGF-ß1, Collagen I and α-SMA, were also decreased by AS-IV. Furthermore, AS-IV relieved the inhibition of tacrolimus on antioxidant enzymes. The data in HK-2 cells also proved that AS-IV reduced tacrolimus-induced cell death and oxidative stress. Mechanistically, AS-IV markedly promoted the nuclear translocation of Nrf2 and the renal protective effects of AS-IV were abolished by Nrf2 inhibitor. Further researches showed that phosphorylated p62 was significantly increased after AS-IV pretreatment. Moreover, AS-IV failed to increase nuclear translocation of Nrf2 and subsequent anti-oxidative stress in HK-2 cells transfected with p62 siRNA. Collectively, these findings indicate that AS-IV relieve TIN by enhancing p62 phosphorylation, thereby increasing Nrf2 nuclear translocation, and then alleviating ROS accumulation and renal fibrosis.

Risk factors and clinical characteristics of tacrolimus-induced acute nephrotoxicity in children with nephrotic syndrome: a retrospective case-control study.

PURPOSE: Acute nephrotoxicity is a common adverse reaction of tacrolimus therapy; however, its risk factors in pediatric nephrotic syndrome (NS) remain to be evaluated. The objective of this study was to investigate the risk factors and characteristics of tacrolimus-induced acute nephrotoxicity in children with NS. METHODS: Past records of children with NS admitted to our hospital from 2014 to 2018 were reviewed. The incidence and characteristics of nephrotoxicity were analyzed. Multivariate logistic regression analysis was used to identify the risk factors of nephrotoxicity. A clinically applicable risk score was developed and validated. RESULTS: Tacrolimus-induced nephrotoxicity occurred in 25 of 129 patients, 13 patients were grade 1, and the renal function was recovered in 22 patients. Multivariate regression analysis showed that the maximum trough concentrations (C12h) of tacrolimus (OR, 1.48; 95% CI, 1.16 to 1.88; P < 0.001), huaiqihuang granules (OR, 0.095; 95% CI, 0.014 to 0.66; P = 0.017), and diarrhea (OR, 22.00; 95% CI, 1.58 to 306.92; P = 0.022) were independently associated with tacrolimus-induced nephrotoxicity. The maximum C12h were significantly higher in patients with nephrotoxicity (median 9.0 ng/ml) and the cut-off value for acute nephrotoxicity was 6.5 ng/ml. The area under the receiver operating characteristic curve was 0.821 for the proposed model based on the observations used to create the model and 0.817 obtained from k-fold cross-validation. CONCLUSIONS: High trough concentration of tacrolimus and diarrhea can potentiate the risk of tacrolimus-induced acute nephrotoxicity in children with NS, while huaiqihuang granules can protect this condition.

Rapid Antidepressant Effect of Hydrogen Sulfide: Evidence for Activation of mTORC1-TrkB-AMPA Receptor Pathways.

AIMS: We asked whether hydrogen sulfide (H2S), as the third gaseous mediator, provided fast antidepressant effect on major depressive disorders and underlying mechanisms. RESULTS: The decreased level of H2S was detected in the hippocampus of chronic unpredictable mild stress (CUMS)-treated rats. Acute administration of H2S either by H2S inhalation or by the donor NaHS produced a rapid antidepressant-like behavioral effect. Further investigation demonstrated that this effect of H2S was mediated by reversing the CUMS-induced decrease in dendritic spine density and required the activation of mammalian target of rapamycin (mTOR)C1 and neurotrophic TrkB receptors, which proceeded to increase synaptic protein expression, including postsynaptic density protein 95, synaptophysin, and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor GluR1/2 subunit. INNOVATION: This study provides the first direct evidence for detecting the decreased H2S in hippocampus of CUMS rats and the biological significance of H2S in treating major depression. CONCLUSION: Our data demonstrate that H2S activates mTORC1 signaling cascades and thereby produces fast-onset antidepressant effect. The study provides a profound insight into H2S or its donors as potent preventive and therapeutic agents for intervention of depression. Antioxid. Redox Signal. 27, 472-488.

Sinomenine Protects PC12 Neuronal Cells against H2O2-induced Cytotoxicity and Oxidative Stress via a ROS-dependent Up-regulation of Endogenous Antioxidant System.

Sinomenine (SN), a purified alkaloid from Chinese herb Sinomenium acutum that was used preferentially in the treatment of rheumatoid diseases, has exerted neuroprotective effects and anti-inflammatory properties in many previous studies. Some studies have revealed that the antioxidant property of SN, acting mainly through inhibiting NADPH oxidase activation, was involved in the beneficial effects of SN. However, SN belongs to the family of dextrorotatory morphinan analogues, which may initiate elevation of reactive oxygen species (ROS) levels. Thus in the present report, we conducted studies to examine its impact and mechanism on the resistance of PC12 neuronal cells to oxidative stress. Precondition with SN (0.1-5 µM) for 12 h significantly decreased H2O2-induced cytotoxicity and remarkably alleviated oxidative injury. However, SN exhibited little direct free radical scavenging property in vitro and induced "appropriate" production of ROS in PC12 cell. Interestingly, the SN-triggering ROS production served as a signal to activate the Nrf2 antioxidant system including Nrf2, HO-1, and NQO-1, which was inhibited by the antioxidant trolox. Furthermore, Nrf2 knockdown largely attenuated the beneficial effects of SN precondition on oxidative stress. In conclusion, our findings suggested that SN increased the resistance to oxidative stress in neuronal cells via a ROS-dependent up-regulation of endogenous antioxidant system, and this mechanism may be involved in the neuroprotection of SN.

Activity-Dependent Sulfhydration Signal Controls N-Methyl-D-Aspartate Subtype Glutamate Receptor-Dependent Synaptic Plasticity via Increasing d-Serine Availability.

AIMS: Reactive sulfur species, including hydrogen sulfide (H2S) and its oxydates, have been raised as novel redox signaling molecules. The present study aimed at examining whether endogenous sulfhydration signal is required for long-term potentiation (LTP), a cellular model for memory. RESULTS: In this study, we found that increased synaptic activity triggered sulfide generation and protein sulfhydration. Activity-triggered sulfide production was essential for N-methyl-D-aspartate subtype glutamate receptor (NMDAR)-dependent LTP via maintaining the availability of d-serine, a primary coagonist for synaptic NMDARs. Genetic knockdown of cystathionine ß-synthase, not cystathionine γ-lyase, impaired LTP. H2S increased NMDAR-dependent LTP via sulfhydration and disinhibition of serine racemase (SR), a main synthetase of d-serine. We found that polysulfides also increased NMDAR-dependent LTP and NMDAR activity. In aged rats, the level of H2S and SR sulfhydration decreased significantly. Exogenous supplement of H2S restored the sulfhydration of SR, followed by the improvement of age-related deficits in LTP. Furthermore, boost of H2S signal in vivo improves hippocampus-dependent memory. Innovation and Conclusion: Our results provide a direct evidence for the biological significance of endogenous sulfhydration signal in synaptic plasticity. Exogenous supplement of H2S could be considered as the new therapeutic approach for the treatment of neurocognitive dysfunction after aging. Antioxid. Redox Signal. 27, 398-414.

Dimethyl sulfide protects against oxidative stress and extends lifespan via a methionine sulfoxide reductase A-dependent catalytic mechanism.

Methionine (Met) sulfoxide reductase A (MsrA) is a key endogenous antioxidative enzyme with longevity benefits in animals. Only very few approaches have been reported to enhance MsrA function. Recent reports have indicated that the antioxidant capability of MsrA may involve a Met oxidase activity that facilities the reaction of Met with reactive oxygen species (ROS). Herein, we used a homology modeling approach to search the substrates for the oxidase activity of MsrA. We found that dimethyl sulfide (DMS), a main metabolite that produced by marine algae, emerged as a good substrate for MsrA-catalytic antioxidation. MsrA bounds to DMS and promoted its antioxidant capacity via facilitating the reaction of DMS with ROS through a sulfonium intermediate at residues Cys72, Tyr103, and Glu115, followed by the release of dimethyl sulfoxide (DMSO). DMS reduced the antimycin A-induced ROS generation in cultured PC12 cells and alleviated oxidative stress. Supplement of DMS exhibited cytoprotection and extended longevity in both Caenorhabditis elegans and Drosophila. MsrA knockdown abolished the cytoprotective effect and the longevity benefits of DMS. Furthermore, we found that the level of physiologic DMS was at the low micromolar range in different tissues of mammals and its level decreased after aging. This study opened a new window to elucidate the biological role of DMS and other low-molecular sulfides in the cytoprotection and aging.

Dimethyl sulfide, a metabolite of the marine microorganism, protects SH-SY5Y cells against 6-hydroxydopamine and MPP+-induced apoptosis / 中国药理学与毒理学杂志

Dimethyl sulfide (DMS) has been historically recognized as a metabolite of the marine microorganism or a disgusting component for the smell of halitosis patients. In our recent study, DMS has been identified as a cytoprotectant that protects against oxidative-stress induced cell death and aging. We found that at near- physiological concentrations, DMS reduced reactive oxygen species (ROS) in cultured PC12 cells and alleviated oxidative stress. The radical-scavenging capacity of DMS at near-physiological concentration was equivalent to endogenous methionine(Met)-centered antioxidant defense. Methionine sulfoxidereductase A (MsrA), the key antioxidant enzyme in Met-centered defense, bound to DMS and promoted its antioxidant capacity via facilitating the reaction of DMS with ROS through a sulfonium intermediate at residues Cys72, Tyr103, Glu115, followed by the release of dimethyl sulfoxide (DMSO). MTT assay and trypan blue test indicated that supplement of DMS exhibited cytopro?tection against 6-hydroxydopamine and MPP + induced cell apoptosis. Furthermore, MsrA knockdown abolished the cytoprotective effect of DMS at near- physiological concentrations. The present study reveals new insight into the potential therapeutic value of DMS in Parkinson disease.

Sulfite triggers sustained calcium overload in cultured cortical neurons via a redox-dependent mechanism.

Sulfite is a compound commonly used as preservative in foods and pharmaceuticals. Many studies have examined the neurotoxicity of sulfite, but its effect on neuronal calcium homeostasis has not yet been reported. Here, we observed the effect of sulfite on the cytosolic free calcium concentration ([Ca(2+)]i) in cultured cortical neurons using Fura-2/AM based calcium imaging technique. Sulfite (250-1000µM) caused a sustained increase in [Ca(2+)]i in the neurons via a dose-dependent manner. In Ca(2+)-free solution, sulfite failed to increase [Ca(2+)]i. After the depletion of the intracellular calcium store, the effect of sulfite on the [Ca(2+)]i was largely abolished. Pharmacological inhibition of phospholipase C (PLC)-inositol 1,4,5-triphosphate (IP3) signaling pathway blocked sulfite-induced increase of [Ca(2+)]i. Interestingly, antioxidants such as trolox and dithiothreitol, abolished the increase of [Ca(2+)]i induced by sulfite. Exposure to sulfite triggered generation of sulfur- and oxygen-centered free radicals in neurons and increased oxidative stress both in the cultured cortical neurons and the prefrontal cortex of rats. Furthemore, sulfite decreased cell viability in cultured cortical neurons via a calcium-dependent manner. Thus, our current study suggests that the redox-dependent calcium overload triggered by sulfite in cortical neuronsmay be involved in its neurotoxicity.

HFS-Triggered AMPK Activation Phosphorylates GSK3ß and Induces E-LTP in Rat Hippocampus In Vivo.

BACKGROUND: The AMP-activated protein kinase (AMPK) is a sensor of cellular energy and nutrient status, with substantial amount of cross talk with other signaling pathways, including its phosphorylation by Akt, PKA, and GSK3ß. AIMS: Various signaling pathways and energy-consuming transport of glutamate receptors subunits are required in synaptic plasticity. However, it is unknown which energy sensors integrate the signaling pathways in these processes. In this article, we elucidated the role of AMPK activation and GSK3ß phosphorylation after HFS during the inducement of early-phase long-term potentiation (E-LTP). METHODS: Synaptic LTP in vivo was induced by high-frequency stimulation (HFS at 200 Hz at a 5-s interval). In addition, phosphorylation of AMPK and glycogen synthase kinase 3ß (GSK3ß) were measured using Western blotting. The amount of hippocampal AMP, ADP and ATP was measured by HPLC. RESULTS: We showed that the phosphorylation of AMPK and GSK3ß was significantly increased by HFS in vivo. HFS-induced AMPK activation occurred via increased (AMP + ADP)/ATP ratio and activation of Ca(2+) /calmodulin-dependent kinase kinase beta (CaMKKß). Pharmacological inhibition of AMPK by compound C (CC) prevented HFS-induced inhibitory phosphorylation of GSK3ß and the induction of LTP in dentate gyrus (DG) area in vivo. CONCLUSIONS: Our findings reveal that HFS-triggered AMPK activation phosphorylates GSK3ß and induces E-LTP in vivo.

Propranolol decreases retention of fear memory by modulating the stability of surface glutamate receptor GluA1 subunits in the lateral amygdala.

BACKGROUND AND PURPOSE: Posttraumatic stress disorder (PTSD) is a mental disorder with enhanced retention of fear memory and has profound impact on quality of life for millions of people worldwide. The ß-adrenoceptor antagonist propranolol has been used in preclinical and clinical studies for the treatment of PTSD, but the mechanisms underlying its potential efficacy on fear memory retention remain to be elucidated. EXPERIMENTAL APPROACH: We investigated the action of propranolol on the retention of conditioned fear memory, the surface expression of glutamate receptor GluA1 subunits of AMPA receptors and synaptic adaptation in the lateral amygdala (LA) of rats. KEY RESULTS: Propranolol attenuated reactivation-induced strengthening of fear retention while reducing enhanced surface expression of GluA1 subunits and restoring the impaired long-term depression in LA. These effects of propranolol were mediated by antagonizing reactivation-induced enhancement of adrenergic signalling, which activates PKA and calcium/calmodulin-dependent protein kinase II and then regulates the trafficking of AMPA receptors via phosphorylation of GluA1 subunits at the C-terminus. Both i.p. injection and intra-amygdala infusion of propranolol attenuated reactivation-induced enhancement of fear retention. CONCLUSIONS AND IMPLICATIONS: Reactivation strengthens fear retention by increasing the level of noradrenaline and promotes the surface expression of GluA1 subunits and the excitatory synaptic transmission in LA. These findings uncover one mechanism underlying the efficiency of propranolol on retention of fear memories and suggest that ß-adrenoceptor antagonists, which act centrally, may be more suitable for the treatment of PTSD.

Methionine sulfoxide reductase A negatively controls microglia-mediated neuroinflammation via inhibiting ROS/MAPKs/NF-κB signaling pathways through a catalytic antioxidant function.

AIMS: Oxidative burst is one of the earliest biochemical events in the inflammatory activation of microglia. Here, we investigated the potential role of methionine sulfoxide reductase A (MsrA), a key antioxidant enzyme, in the control of microglia-mediated neuroinflammation. RESULTS: MsrA was detected in rat microglia and its expression was upregulated on microglial activation. Silencing of MsrA exacerbated lipopolysaccharide (LPS)-induced activation of microglia and the production of inflammatory markers, indicating that MsrA may function as an endogenous protective mechanism for limiting uncontrolled neuroinflammation. Application of exogenous MsrA by transducing Tat-rMsrA fusion protein into microglia attenuated LPS-induced neuroinflammatory events, which was indicated by an increased Iba1 (a specific microglial marker) expression and the secretion of pro-inflammatory cytokines, and this attenuation was accompanied by inhibiting multiple signaling pathways such as p38 and ERK mitogen-activated protein kinases (MAPKs) and nuclear factor kappaB (NF-κB). These effects were due to MsrA-mediated reactive oxygen species (ROS) elimination, which may be derived from a catalytic effect of MsrA on the reaction of methionine with ROS. Furthermore, the transduction of Tat-rMsrA fusion protein suppressed the activation of microglia and the expression of pro-inflammatory factors in a rat model of neuroinflammation in vivo. INNOVATION: This study provides the first direct evidence for the biological significance of MsrA in microglia-mediated neuroinflammation. CONCLUSION: Our data provide a profound insight into the role of endogenous antioxidative defense systems such as MsrA in the control of microglial function.

Pharmacokinetics of silybin nanoparticles in mice bearing SKOV-3 human ovarian carcinoma xenocraft.

The particle fabrication technique was used to fabricate monodisperse size and shape specific poly (lactide-co-glycolide) particles loaded with the silybin. Response surface methodology (RSM) using the central composite rotatable design (CCRD) model was used to optimize formulations of silybin nanoparticles. Further the optimized nanoparticles are characterized for particle size, zeta potential, surface morphology, entrapment efficiency, in-vitro drug release, silybin availability for tumor, plasma, lung, spleen, liver were determined. The significant findings were the optimal formulation of PLGA concentration 10 mg, PVA concentration 2000 and PET width of 6 gave rise to the EE of 88%, mean diameter of 223 nm and zeta potential of 25-mV. Release studies were investigated at pH 1.2 and pH 6.8. It was studied that lower the pH, faster the release of sylibin. The nanoparticles had~15-fold higher plasma exposure as measured by AUC contrasted to pure silybin. The nanoparticles had a 60% increase altogether tumor silybin presentation contrasted with pure silybin. Nanoparticles had higher silybin presentation in the spleen and liver contrasted with pure silybin suspension as expected for a nanoparticle formulation. The lung silybin presentation for the nanoparticle was additionally 2-fold higher than that of the pure silybin suspension. The results of pharmacokinetic parameters and oral bioavailability data exhibited that drug-nanoparticle complex could enhance the oral absorption of silybin and as well as the use of particles with smaller feature size may be preferred to decrease clearance by organs of the mononuclear phagocyte system.

Regulation of emotional memory by hydrogen sulfide: role of GluN2B-containing NMDA receptor in the amygdala.

As an endogenous gaseous molecule, hydrogen sulfide (H2 S) has attracted extensive attention because of its multiple biological effects. However, the effect of H2 S on amygdala-mediated emotional memory has not been elucidated. Here, by employing Pavlovian fear conditioning, an animal model widely used to explore the neural substrates of emotion, we determined whether H2 S could regulate emotional memory. It was shown that the H2 S levels in the amygdala of rats were significantly elevated after cued fear conditioning. Both intraamygdala and systemic administrations of H2 S markedly enhanced amygdala-dependent cued fear memory in rats. Moreover, it was found that H2 S selectively increased the surface expression and currents of NMDA-type glutamate receptor subunit 2B (GluN2B)-containing NMDA receptors (NMDARs) in lateral amygdala of rats, whereas blockade of GluN2B-containing NMDARs in lateral amygdala eliminated the effects of H2 S to enhance amygdalar long-term potentiation and cued fear memory. These results demonstrate that H2 S can regulate amygdala-dependent emotional memory by promoting the function of GluN2B-containing NMDARs in amygdala, suggesting that H2 S-associated signaling may hold potential as a new target for the treatment of emotional disorders. In our study, the effect of hydrogen sulfide (H2 S) on amygdala-mediated emotional memory was investigated. It was found that H2 S could enhance amygdala-dependent emotional memory and long-term potentiation (LTP) in rats by selectively increasing the function of GluN2B-containing NMDA receptors in the amygdala. These results suggest that H2 S-associated signaling may be a new target for the treatment of emotional disorders.

[Pharmacophore identification of novel dual-target compounds targeting AChE and PARP-1].

Multi-target drugs attract increasing attentions for the therapy of complicated neurodegenerative diseases. In this study, a computer-assisted strategy was applied to search for multi-target compounds by the pharmacophore matching. This strategy has been successfully used to design dual-target inhibitor models against both the acetylcholinesterase (AChE) and poly (ADP-ribose) polymerase-1 (PARP-1). Based on two pharmacophore models matching and physicochemical properties filtering, one hit was identified which could inhibit AChE with IC50 value of (0.337 +/- 0.052) micromol x L(-1) and PARP-1 by 24.6% at 1 micromol x L(-1).