Curcumin reduces myocardial ischemia-reperfusion injury, by increasing endogenous H2S levels and further modulating m6A.

BACKGROUND: Our previous research shows that Curcumin (CUR) attenuates myocardial ischemia-reperfusion injury (MIRI) by reducing intracellular total RNA m6A levels. However, the mechanism remains unknown. METHODS: For ischemia-reperfusion (IR), H9c2 cells were cultured for 6 h in serum-free low-glycemic (1 g/L) medium and a gas environment without oxygen, and then cultured for 6 h in high-glycemic (4.5 g/L) medium supplemented with 10% FBS and a 21% oxygen environment. The effects of different concentrations of CUR (5, 10, and 20 µM) treatments on signaling molecules in conventionally cultured and IR-treated H9c2 cells were examined. RESULTS: CUR treatment significantly up-regulated the H2S levels, and the mRNA and protein expression of cystathionine γ-lyase (CSE), and down-regulated the mRNAs and proteins levels of thiosulfate sulfurtransferase (TST) and ethylmalonic encephalopathy 1 (ETHE1) in H9c2 cells conventionally cultured and subjected to IR. Exogenous H2S supply (NaHS and GYY4137) significantly reduced intracellular total RNA m6A levels, and the expression of RNA m6A "writers" METTL3 and METTL14, and increased the expression of RNA m6A "eraser" FTO in H9c2 cells conventionally cultured and subjected to IR. CSE knockdown counteracted the inhibitory effect of CUR treatment on ROS production, promotion on cell viability, and inhibition on apoptosis of H9c2 cells subjected to IR. CONCLUSION: CUR attenuates MIRI by regulating the expression of H2S level-regulating enzymes and increasing the endogenous H2S levels. Increased H2S levels could regulate the m6A-related proteins expression and intracellular total RNA m6A levels.

One-Step Synthesis of Polyethyleneimine-Grafted Styrene-Maleic Anhydride Copolymer Adsorbents for Effective Adsorption of Anionic Dyes.

Wastewater containing organic dyes has become one of the important challenges in water treatment due to its high salt content and resistance to natural degradation. In this work, a novelty adsorbent, PEI-SMA, was prepared by grafting polyethyleneimine (PEI) onto styrene-maleic anhydride copolymer (SMA) through an amidation reaction. The various factors, such as pH, adsorbent dosage, contact time, dye concentration, and temperature, which may affect the adsorption of PEI-SMA for Reactive Black 5 (RB5), were systematically investigated by static adsorption experiments. The adsorption process of PEI-SMA for RB5 was more consistent with the Langmuir isotherm model and the pseudo-second-order model, suggesting a single-layer chemisorption. PEI-SMA exhibits excellent adsorption performance for RB5 dye, with a maximum adsorption capacity of 1749.19 mg g-1 at pH = 2. Additionally, PEI-SMA exhibited highly efficient RB5 competitive adsorption against coexisting Cl- and SO42- ions and cationic dyes. The adsorption mechanism was explored, and it can be explained as the synergistic effect of electrostatic interaction, hydrogen bonding and π-π interaction. This study demonstrates that PEI-SMA could act as a high performance and promising candidate for the effective adsorption of anionic dyes from aqueous solutions.

Discrepancy of synaptic and microtubular protein phosphorylation in the hippocampus of APP/PS1 and MAPT×P301S transgenic mice at the early stage of Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, and is caused by multiple pathological factors, such as the overproduction of ß-amyloid (Aß) and the hyperphosphorylation of tau. However, there is limited knowledge of the mechanisms underlying AD pathogenesis and no effective biomarker for the early diagnosis of this disorder. Thus in this study, a quantitative phosphoproteomics analysis was performed to evaluate global protein phosphorylation in the hippocampus of Aß overexpressing APP/PS1 transgenic mice and tau overexpressing MAPT×P301S transgenic mice, two in vivo AD model systems. These animals, up to ten weeks old, do not exhibit cognitive dysfunctions and are widely used to simulate early-stage AD patients. The number of differentially phosphorylated proteins (DPPs) was greater for APP/PS1 transgenic mice than for MAPT×P301S transgenic mice. The function of the DPPs in APP/PS1 transgenic mice was mainly related to synapses, while the function of the DPPs in MAPT×P301S transgenic mice was mainly related to microtubules. In addition, an AD core network was established including seven phosphoproteins differentially expressed in both animal models, and the function of this core network was related to synapses and oxidative stress. The results of this study suggest that Aß and tau induce different protein phosphorylation profiles in the early stage of AD, leading to the dysfunctions in synapses and microtubule, respectively. And the detection of same DPPs in these animal models might be used for early AD diagnosis.

Elucidation of Pharmacological Mechanism Underlying the Anti-Alzheimer's Disease Effects of Evodia rutaecarpa and Discovery of Novel Lead Molecules: An In Silico Study.

Alzheimer's disease (AD) is a brain disease with a peculiarity of multiformity and an insidious onset. Multiple-target drugs, especially Chinese traditional medicine, have achieved a measure of success in AD treatment. Evodia rutaecarpa (Juss.) Benth. (Wuzhuyu, WZY, i.e., E. rutaecarpa), a traditional Chinese herb, has been identified as an effective drug to cure migraines. To our surprise, our in silico study showed that rather than migraines, Alzheimer's disease was the primary disease to which the E. rutaecarpa active compounds were targeted. Correspondingly, a behavioral experiment showed that E. rutaecarpa extract could improve impairments in learning and memory in AD model mice. However, the mechanism underlying the way that E. rutaecarpa compounds target AD is still not clear. For this purpose, we employed methods of pharmacology networking and molecular docking to explore this mechanism. We found that E. rutaecarpa showed significant AD-targeting characteristics, and alkaloids of E. rutaecarpa played the main role in binding to the key nodes of AD. Our research detected that E. rutaecarpa affects the pathologic development of AD through the serotonergic synapse signaling pathway (SLC6A4), hormones (PTGS2, ESR1, AR), anti-neuroinflammation (SRC, TNF, NOS3), transcription regulation (NR3C1), and molecular chaperones (HSP90AA1), especially in the key nodes of PTGS2, AR, SLCA64, and SRC. Graveoline, 5-methoxy-N, N-dimethyltryptamine, dehydroevodiamine, and goshuyuamide II in E. rutaecarpa show stronger binding affinities to these key proteins than currently known preclinical and clinical drugs, showing a great potential to be developed as lead molecules for treating AD.

Reduction of Tet2 exacerbates early stage Alzheimer's pathology and cognitive impairments in 2×Tg-AD mice.

Abnormal modification of 5-hydroxymethylcytosine (5hmC) is closely related to the occurrence of Alzheimer's disease (AD). However, the role of 5hmC and its writers, ten-eleven translocation (Tet) proteins, in regulating the pathogenesis of AD remains largely unknown. We detected a significant decrease in 5hmC and Tet2 levels in the hippocampus of aged APPswe/PSEN1 double-transgenic (2×Tg-AD) mice that coincides with abundant amyloid-ß (Aß) plaque accumulation. On this basis, we examined the reduction of Tet2 expression in the hippocampus at early disease stages, which caused a decline of 5hmC levels and led young 2×Tg-AD mice to present with advanced stages of AD-related pathological hallmarks, including Aß accumulation, GFAP-positive astrogliosis and Iba1-positive microglia overgrowth as well as the overproduction of pro-inflammatory factors. Additionally, the loss of Tet2 in the 2×Tg-AD mice at 5 months of age accelerated hippocampal-dependent learning and memory impairments compared to age-matched control 2×Tg-AD mice. In contrast, restoring Tet2 expression in adult neural stem cells isolated from aged 2×Tg-AD mice hippocampi increased 5hmC levels and increased their regenerative capacity, suggesting that Tet2 might be an exciting target for rejuvenating the brain during aging and AD. Further, hippocampal RNA sequencing data revealed that the expression of altered genes identified in both Tet2 knockdown and control 2×Tg-AD mice was significantly associated with inflammation response. Finally, we demonstrated that Tet2-mediated 5hmC epigenetic modifications regulate AD pathology by interacting with HDAC1. These results suggest a combined approach for the regulation and treatment of AD-related memory impairment and cognitive symptoms by increasing Tet2 via HDAC1 suppression.

Role of Ten eleven translocation-2 (Tet2) in modulating neuronal morphology and cognition in a mouse model of Alzheimer's disease.

Abnormal expression of Ten eleven translocation-2 (Tet2) contributes to the pathogenesis of Alzheimer's disease (AD). However, to date, the role of Tet2 in modulating neuronal morphology upon amyloid-ß (Aß)-induced neurotoxicity has not been shown in a mouse model of AD. Here, we have developed a model of injured mouse hippocampal neurons induced by Aß42 oligomers in vitro. We also investigated the role of Tet2 in injured neurons using recombinant plasmids-induced Tet2 inhibition or over-expression. We found that the reduced expression of Tet2 exacerbated neuronal damage, whereas the increased expression of Tet2 was sufficient to protect neurons against Aß42 toxicity. Our results indicate that the brains of aged APPswe/PSEN1 double-transgenic (2 × Tg-AD) mice exhibit an increase in Aß plaque accumulation and a decrease in Tet2 expression. As a result, we have also explored the underlying mechanisms of Tet2 in cognition and amyloid load in 2 × Tg-AD mice via adeno-associated virus-mediated Tet2 knockdown or over-expression. Recombinant adeno-associated virus was microinjected into bilateral dentate gyrus regions of the hippocampus of the mice. Knocking down Tet2 in young 2 × Tg-AD mice resulted in the same extent of cognitive dysfunction as aged 2 × Tg-AD mice. Importantly, in middle-aged 2 × Tg-AD mice, knocking down Tet2 accelerated the accumulation of Aß plaques, whereas over-expressing Tet2 alleviated amyloid burden and memory loss. Furthermore, our hippocampal RNA-seq data, from young 2 × Tg-AD mice, were enriched with aberrantly expressed lncRNAs and miRNAs that are modulated by Tet2. Tet2-modulated lncRNAs (Malat1, Meg3, Sox2ot, Gm15477, Snhg1) and miRNAs (miR-764, miR-211, and miR-34a) may play a role in neuron formation. Overall, these results indicate that Tet2 may be a potential therapeutic target for repairing neuronal damage and cognitive impairment in AD.

A natural product of acteoside ameliorate kidney injury in diabetes db/db mice and HK-2 cells via regulating NADPH/oxidase-TGF-ß/Smad signaling pathway.

This study was designed to investigate the protective effects and mechanisms of acteoside on DKD in diabetes male db/db mice and high glucose-induced HK-2 cells. The diabetes db/db mice were divided randomly into model group, metformin group, irbesartan group, and acteoside group. We observed the natural product of acteoside exhibiting a significant effect in renal protection through analyzing of biochemical indicators and endogenous metabolites, histopathological observations, and western blotting. HK-2 cells subjected to high glucose were used in invitro experiments. The molecular mechanisms of them were investigated by RT-PCR and western blot. Acteoside prevents high glucose-induced HK-2 cells and diabetes db/db mice by inhibiting NADPH/oxidase-TGF-ß/Smad signaling pathway. Acteoside regulated the disturbed metabolic pathway of lipid metabolism, glyoxylate and dicarboxylate metabolism, and arachidonic acid metabolism. We discovered the natural product of acteoside exhibiting a significant effect in renal protection. This study paved the way for further exploration of pathogenesis, early diagnosis, and development of a new therapeutic agent for DKD.

Two-Dimensional Organic-Inorganic Hybrid Rare-Earth Double Perovskite Ferroelectrics.

As a major branch of hybrid perovskites, two-dimensional (2D) hybrid double perovskites are expected to be ideal systems for exploring novel ferroelectric properties, because they can accommodate a variety of organic cations and allow diverse combinations of different metal elements. However, no 2D hybrid double perovskite ferroelectric has been reported since the discovery of halide double perovskites in the 1930s. Based on trivalent rare-earth ions and chiral organic cations, we have designed a new family of 2D rare-earth double perovskite ferroelectrics, A4MIMIII(NO3)8, where A is the organic cation, MI is the alkaline metal or ammonium ion, and MIII is the rare-earth ion. This is the first time that ferroelectricity is realized in 2D hybrid double perovskite systems. These ferroelectrics have achieved high-temperature ferroelectricity and photoluminescent properties. By varying the rare-earth ion, variable photoluminescent properties can be achieved. The results reveal that the 2D rare-earth double perovskite systems provide a promising platform for achieving multifunctional ferroelectricity.

Pharmacological Mechanisms Underlying the Neuroprotective Effects of Alpinia oxyphylla Miq. on Alzheimer's Disease.

Alpinia oxyphylla Miq. (i.e., A. oxyphylla), a traditional Chinese medicine, can exert neuroprotective effects in ameliorating mild cognitive impairment and improving the pathological hallmarks of Alzheimer's disease (AD). Here, 50 active compounds and 164 putative targets were collected and identified with 251 clinically tested AD-associated target proteins using network pharmacology approaches. Based on the Gene Ontology/Kyoto Encyclopedia of Genes and Genomes pathway enrichments, the compound-target-pathway-disease/protein-protein interaction network constructions, and the network topological analysis, we concluded that A. oxyphylla may have neuroprotective effects by regulating neurotransmitter function, as well as brain plasticity in neuronal networks. Moreover, closely-related AD proteins, including the amyloid-beta precursor protein, the estrogen receptor 1, acetylcholinesterase, and nitric oxide synthase 2, were selected as the bottleneck nodes of network for further verification by molecular docking. Our analytical results demonstrated that terpene, as the main compound of A. oxyphylla extract, exerts neuroprotective effects, providing new insights into the development of a natural therapy for the prevention and treatment of AD.

Hybrid Organic-Inorganic Antiperovskites.

Substitution of A-site and/or X-site ions of ABX3 -type perovskites with organic groups can give rise to hybrid perovskites, many of which display intriguing properties beyond their parent compounds. However, this method cannot be extended effectively to hybrid antiperovskites. Now, the design of hybrid antiperovskites under the guidance of the concept of Goldschmidt's tolerance factor is presented. Spherical anions were chosen for the A and B sites and spherical organic cations for the X site, and seven hybrid antiperovskites were obtained, including (F3 (H2 O)x )(AlF6 )(H2 dabco)3 , ((Co(CN)6 )(H2 O)5 )(MF6 )(H2 dabco)3 (M=Al3+ , Cr3+ , or In3+ ), (Co(CN)6 )(MF6 )(H2 pip)3 (M=Al3+ or Cr3+ ), and (SbI6 )(AlF6 )(H2 dabco)3 . These new structures reveal that all ions at A, B, and X sites of inorganic antiperovskites can be replaced by molecular ions to form hybrid antiperovskites. This work will lead to the synthesis of a large family of hybrid antiperovskites.

SSeCKS promoted lipopolysaccharide-sensitized astrocytes migration via increasing ß-1,4-galactosyltransferase-I activity.

Astrocytes migration is essential in the formation of the glial scar during the injury response process of the central nervous system (CNS) especially during inflammation. Integrin ß1 is part of the extracellular matrix receptors in the CNS and it has been reported that integrin ß-deficient astrocytes randomly migrate into wounds. Previous studies have found that ß-1,4 Galactosyltransferase-I (ß-1,4-GalT-I) enhanced the ß-1,4-galactosylation of integrin ß1. Src-suppressed C kinase substrate (SSeCKS) is an inflammatory response protein which functionally interacts with ß-1,4 Galactosyltransferase-I (ß-1,4-GalT-I). In this study we aim to investigate the role of SSeCKS and ß-1,4-GalT-I in the migration of astrocytes during lipopolysaccharide (LPS)-induced inflammation. Coimmunoprecipitation and immunofluorescence assays have demonstrated that SSeCKS and ß-1,4-GalT-I were significantly enhanced in LPS-treated astrocytes and their interactions may occur in the Trans-Golgi Network. Lectin blot showed that the knockdown of ß-1,4-GalT-I could inhibit the ß-1,4-galactosylation of glycoproteins including integrin ß1 with and without LPS, and that SSeCKS knockdown inhibits the ß-1,4-galactosylation of glycoproteins including integrin ß1 only in LPS-induced astrocytes. Additionally, wound healing assays indicated that ß-1,4-GalT-I knockdown could inhibit astrocytes migration with and without LPS but SSeCKS inhibited cell migration only when LPS was present. Therefore our findings suggest that SSeCKS affects astrocytes migration by regulating the ß-1,4-galactosylation of glycoproteins including integrin ß1, via ß-1,4-GalT-I expression in LPS-sensitized astrocytes.

Association of multiple candidate genes with mild cognitive impairment in an elderly Chinese Uygur population in Xinjiang.

BACKGROUND: Mild cognitive impairment (MCI) is a high-risk factor for Alzheimer's disease (AD). In the present study, we investigated the association of genetic polymorphisms of five genes (8-oxoguanine DNA glycosylase 1 (OGG1), bridging integrator 1 (BIN1), sortilin-related receptor 1 (SORL1), presenilin 2 (PSEN2) and nerve growth factor (NGF)) with MCI risk in a Xinjiang Uygur population. We also tested the relationship between the promoter methylation of genes OGG1 and dihydrolipoamide S-succinyltransferase (DLST) with MCI. METHODS: This study involved 43 MCI patients and 125 controls. Genotyping was done by Sanger sequencing. DNA methylation assays used quantitative methylation-specific polymerase chain reaction. RESULTS: We found that polymorphisms of five genes and the methylation of DLST and OGG1 genes were not associated with MCI (P > 0.05). Further subgroup analysis found that DLST hypomethylation was significantly associated with MCI in the carriers of apolipoprotein E (APOE) ε4 (P = 0.042). In the carriers of non-APOE ε4, DLST methylation levels were significantly lower in the male control group than in the female control group (p = 0.04). Meanwhile, among the non-APOE ε4 carriers younger than 75, OGG1 hypermethylation levels were significantly associated with MCI (P = 0.049). DLST methylation in female controls was significantly lower than that in male controls (P = 0.003). According to gender stratification, there was a significant positive correlation of fasting plasma glucose (FBG) and high-density lipoprotein (HDL) with OGG1 methylation in the female controls (FBG: P = 0.024; HDL: P = 0.033). There was a significant inverse correlation between low-density lipoprotein and DLST methylation in male MCI (P = 0.033). There was a significant positive correlation between HDL and DLST methylation levels in the female controls (P = 0.000). CONCLUSIONS: This study was the first to discover that DLST promoter methylation interacted with APOE ε4 and thus affected the pathogenesis of MCI. In addition, OGG1 promoter methylation interacted with several other factors to increase the risk of MCI.

Enhancing Mechanical Properties of Flexible Graphene/ Cellulose Conductive Paper by Chemically Modifying Cellulose Fibers.

In recent years, conductive paper made of graphene and cellulose fibers has triggered a great deal of attention due to its scalable fabrication process, low cost, and environmentally friendliness. However, poor mechanical properties limit its commercial applications. In this study, conductive graphene/cellulose paper with improved elastic modulus and desirable conductivity was achieved by chemically modifying the surface properties of natural cellulose fibers using aqueous 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) oxidation system. The effect of the carboxyl content on the mechanical properties and conductivity of graphene/cellulose paper was studied in detail. The results showed that the carboxyl content of cellulose had a significant impact on the mechanical properties of graphene/cellulose paper. At low carboxyl content (0.42 mmol/g), the elastic modulus of the graphene/oxidized-cellulose conductive paper achieved the value of 1572 MPa, which was 27.4% larger than that of cellulose/graphene conductive paper. Meanwhile, the as-prepared paper exhibited excellent conductive properties, and its sheet resistance was only 78.57 Ω/sq.

Taxifolin prevents ß-amyloid-induced impairments of synaptic formation and deficits of memory via the inhibition of cytosolic phospholipase A2/prostaglandin E2 content.

Taxifolin is a potent flavonoid with anti-inflammatory activity. Taxifolin has been reported to decrease the accumulation of ß-amyloid (Aß), and reduce Aß-induced neurotoxicity. However, the detail molecular mechanism of taxifolin against Aß-induced neurotoxicity is largely unknown. In this study, we revealed the protective effects and the underlying mechanisms of taxifolin on the impairments of cognitive function and synapse formation induced by soluble Aß oligomers. Our results showed that taxifolin prevented neuronal cell death in a concentration-dependent manner. The recognition memory in novel object recognition tasks and the spatial memory in Morris water maze tests are significantly lower in the Alzheimer's disease (AD) model mice induced by hippocampal injection of Aß42. Taxifolin treatment prevented the recognitive and spatial memory deficits of the AD mice. 10 mg/kg taxifolin treatment also significantly prevented the decreased expression levels of PSD 95 induced by Aß42. Live cell imaging study showed that 2 h pre-treatment of taxifolin prevented the decrease in the number of filopodium and spine induced by Aß42 oligomers. Aß42 oligomers significantly increased the production of cytosolic phospholipase A2 (cPLA2), a crucial enzyme of pro-inflammatory mediator, and prostaglandin E2 (PGE2), a neuroinflammatory molecule. Taxifolin significantly reduced the content of cPLA2 and PGE2 induced by Aß42 both in the primary hippocampal neurons and hippocampal tissues. These results indicated that taxifolin might prevent Aß42 oligomer-induced synapse and cognitive impairments through decreasing cPLA2 and PGE2. Our study provided novel insights into the cellular mechanisms for the protective effects of taxifolin on AD.

Tacrine(10)-hupyridone, a dual-binding acetylcholinesterase inhibitor, potently attenuates scopolamine-induced impairments of cognition in mice.

Tacrine(10)-hupyridone (A10E) was designed as a dual-binding acetylcholinesterase (AChE) inhibitor from the modification of tacrine and a fragment of huperzine A. We have found that A10E effectively inhibited AChE in a mixed competitive manner, with an IC50 of 26.4 nM, which is more potent than those of tacrine and huperzine A. Most importantly, we have shown, for the first time that A10E attenuated scopolamine-induced cognitive impairments without affecting motor function in mice. A10E effectively attenuated impairments of learning and memory to a similar extent as donepezil, an inhibitor of AChE used for treating Alzheimer's disease (AD). In addition, A10E significantly decreased AChE activity in the brain of mice, suggesting that A10E might cross the brain blood-barrier. Taken together, our results demonstrated that A10E, a designed dual-binding AChE inhibitor, could effectively reverse cognitive impairments, indicating that A10E might provide therapeutic efficacy for AD treatment.

Indirubin-3-Oxime Prevents H2O2-Induced Neuronal Apoptosis via Concurrently Inhibiting GSK3ß and the ERK Pathway.

Oxidative stress-induced neuronal apoptosis plays an important role in many neurodegenerative disorders. In this study, we have shown that indirubin-3-oxime, a derivative of indirubin originally designed for leukemia therapy, could prevent hydrogen peroxide (H2O2)-induced apoptosis in both SH-SY5Y cells and primary cerebellar granule neurons. H2O2 exposure led to the increased activities of glycogen synthase kinase 3ß (GSK3ß) and extracellular signal-regulated kinase (ERK) in SH-SY5Y cells. Indirubin-3-oxime treatment significantly reversed the altered activity of both the PI3-K/Akt/GSK3ß cascade and the ERK pathway induced by H2O2. In addition, both GSK3ß and mitogen-activated protein kinase inhibitors significantly prevented H2O2-induced neuronal apoptosis. Moreover, specific inhibitors of the phosphoinositide 3-kinase (PI3-K) abolished the neuroprotective effects of indirubin-3-oxime against H2O2-induced neuronal apoptosis. These results strongly suggest that indirubin-3-oxime prevents H2O2-induced apoptosis via concurrent inhibiting GSK3ß and the ERK pathway in SH-SY5Y cells, providing support for the use of indirubin-3-oxime to treat neurodegenerative disorders caused or exacerbated by oxidative stress.

SB203580 reverses memory deficits and depression-like behavior induced by microinjection of Aß1-42 into hippocampus of mice.

A high co-morbidity between Alzheimer's disease (AD) and depression suggests there might be similar mechanisms underlying the course of these diseases. Previous studies have shown that p38MAPK plays a critical role in the pathophysiology of AD and depression. However, little is known about whether SB203580, a selective inhibitor of p38MAPK, may protect against AD-associated cognitive impairments and depression-like behavior, simultaneously. Herein, we have shown, for the first time, that SB203580 may reverse memory impairments and depression-like behavior induced by hippocampal infusion of ß-amyloid 1-42 (Aß1-42), as measured by novel object recognition, Morris water maze, tail-suspension and forced-swimming tests. In addition, phorbol 12-myristate 13-acetate (PMA), a PKC activator which also activates p38MAPK, significantly abolished the effects of SB203580. Moreover, Aß1-42 causes increased phosphorylation of p38MAPK and decreased phosphorylation of Ser9-glycogen synthase kinase 3ß (GSK3ß) and cAMP-response element binding protein (CREB) in the hippocampus of mice, which could be significantly reversed by SB203580. Our results suggest that SB203580 reversed Aß1-42-induced cognitive impairments and depression-like behavior via inhibiting p38MAPK signaling pathway, which not only supports p38MAPK as a therapeutic target for AD-associated cognitive dysfunction and depression-like behavior, but also provides experimental basis for the use of SB203580 in co-morbidity of AD and depression.

Curcumin attenuates surgery-induced cognitive dysfunction in aged mice.

Post-operative cognitive dysfunction (POCD) is associated with elderly patients undergoing surgery. However, pharmacological treatments for POCD are limited. In this study, we found that curcumin, an active compound derived from Curcuma longa, ameliorated the cognitive dysfunction following abdominal surgery in aged mice. Further, curcumin prevented surgery-induced anti-oxidant enzyme activity. Curcumin also increased brain-derived neurotrophic factor (BDNF)-positive area and expression of pAkt in the brain, suggesting that curcumin activated BDNF signaling in aged mice. Furthermore, curcumin neutralized cholinergic dysfunction involving choline acetyltransferase expression induced by surgery. These results strongly suggested that curcumin prevented cognitive impairments via multiple targets, possibly by increasing the activity of anti-oxidant enzymes, activation of BDNF signaling, and neutralization of cholinergic dysfunction, concurrently. Based on these novel findings, curcumin might be a potential agent in POCD prophylaxis and treatment.

5-Hydroxycyclopenicillone, a New ß-Amyloid Fibrillization Inhibitor from a Sponge-Derived Fungus Trichoderma sp. HPQJ-34.

Abstract: A new cyclopentenone, 5-hydroxycyclopeni cillone (1), was isolated together with three known compounds, ar-turmerone (2), citreoisocoumarin (3), and 6-O-methyl-citreoisocoumarin (4), from a culture of the sponge-derived fungus Trichoderma sp. HPQJ-34. The structures of 1-4 were characterized using comprehensive spectroscopic analyses. The absolute configuration of 1 was determined by comparison of electronic circular dichroism (ECD) spectra with literature values used for the reported analogue, cyclopenicillone (5), which was not isolated in this research. Compound 1 was shown to scavenge 2,2-diphenyl-1-picrylhydrazyl free radicals, and decrease ß-amyloid (Aß) fibrillization in vitro. Moreover, 1 significantly reduced H2O2-induced neurotoxicity in SH-SY5Y cells. These findings suggested that compound 1, a newly discovered cyclopentenone, has moderate anti-oxidative, anti-Aß fibrillization properties and neuroprotective effects, and might be a good free radical scavenger.

The Rapid Effect of Bisphenol-A on Long-Term Potentiation in Hippocampus Involves Estrogen Receptors and ERK Activation.

Bisphenol-A (BPA), a widely used synthetic compound in plastics, disrupts endocrine function and interferes with physiological actions of endogenous gonadal hormones. Chronic effects of BPA on reproductive function, learning and memory, brain structure, and social behavior have been intensively investigated. However, less is known about the influence of BPA on long-term potentiation (LTP), one of the major cellular mechanisms that underlie learning and memory. In the present study, for the first time we investigated the effect of different doses of BPA on hippocampal LTP in rat brain slices. We found a biphasic effect of BPA on LTP in the dentate gyrus: exposure to BPA at a low dose (100 nM) enhanced LTP and exposure to BPA at a high dose (1000 nM) inhibited LTP compared with vehicle controls. The rapid facilitatory effect of low-dose BPA on hippocampal LTP required membrane-associated estrogen receptor (ER) and involved activation of the extracellular signal-regulated kinase (ERK) signaling pathway. Coadministration of 17ß-estradiol (E2, the primary estrogen hormone) and BPA (100 nM) abolished both the BPA-induced enhancement of LTP and the E2-induced enhancement of baseline fEPSP, suggesting a complex interaction between BPA- and E2-mediated signaling pathways. Our investigation implies that even nanomolar levels of endocrine disrupters (e.g., BPA) can induce significant effects on hippocampal LTP.