Prmt7 regulates the JAK/STAT/Socs3 signaling pathway in postmenopausal cardiomyopathy.

Protein arginine methyltransferases (PRMTs) modulate diverse cellular processes, including stress responses. The present study explored the role of Prmt7 in protecting against menopause-associated cardiomyopathy. Mice with cardiac-specific Prmt7 ablation (cKO) exhibited sex-specific cardiomyopathy. Male cKO mice exhibited impaired cardiac function, myocardial hypertrophy, and interstitial fibrosis associated with increased oxidative stress. Interestingly, female cKO mice predominantly exhibited comparable phenotypes only after menopause or ovariectomy (OVX). Prmt7 inhibition in cardiomyocytes exacerbated doxorubicin (DOX)-induced oxidative stress and DNA double-strand breaks, along with apoptosis-related protein expression. Treatment with 17ß-estradiol (E2) attenuated the DOX-induced decrease in Prmt7 expression in cardiomyocytes, and Prmt7 depletion abrogated the protective effect of E2 against DOX-induced cardiotoxicity. Transcriptome analysis of ovariectomized wild-type (WT) or cKO hearts and mechanical analysis of Prmt7-deficient cardiomyocytes demonstrated that Prmt7 is required for the control of the JAK/STAT signaling pathway by regulating the expression of suppressor of cytokine signaling 3 (Socs3), which is a negative feedback inhibitor of the JAK/STAT signaling pathway. These data indicate that Prmt7 has a sex-specific cardioprotective effect by regulating the JAK/STAT signaling pathway and, ultimately, may be a potential therapeutic tool for heart failure treatment depending on sex.

Antimicrobial activity, surface properties, and cytotoxicity of microencapsulated phytochemicals incorporated into three-dimensionally printable dental polymers.

OBJECTIVES: This study aimed to investigate the antimicrobial properties of three dimensionally-printed dental polymers (3DPs) incorporated with microencapsulated phytochemicals (MPs) and to assess their surface characteristics and cytotoxicity. METHODS: MPs derived from phytoncide oil and their specific chemical components were introduced into suspensions of three microbial species: Streptococcus gordonii, Streptococcus oralis, and Candida albicans. Optical density was measured to determine the microbial growth in the presence of MPs for testing their antimicrobial activity. MPs at 5% (w/w) were mixed with dental polymers and dispersants to 3DP discs. These microbial species were then seeded onto the discs and incubated for 24 h. The antibacterial and antifungal activities of MP-containing 3DPs were evaluated by counting the colony-forming units (n = 3). The biofilm formation on the 3DP was assessed by crystal violet staining assay (n = 3). Microbial viability was determined using a live-dead staining and CLSM observation (n = 3). Surface roughness and water contact angle were assessed (n = 10). Cytotoxicity of MP-containing 3DPs for human gingival fibroblast was evaluated by MTT assay. RESULTS: MPs, particularly (-)-α-pinene, suppressed the growth of all tested microbial species. MP-containing 3DPs significantly reduced the colony count (P ≤ 0.001) and biofilm formation (P ≤ 0.009), of all tested microbial species. Both surface roughness (P < 0.001) and water contact angle (P < 0.001) increased. The cytotoxicity remained unchanged after incorporating MPs to the 3DPs (P = 0.310). CONCLUSIONS: MPs effectively controlled the microbial growth on 3DPs as evidenced by the colony count, biofilm formation, and cell viability. Although MPs modified the surface characteristics, they did not influence the cytotoxicity of 3DPs. CLINICAL SIGNIFICANCE: Integration of MPs into 3DPs could produce dental prostheses or appliances with antimicrobial properties. This approach not only provides a proactive solution to reduce the risk of oral biofilm-related infection but also ensures the safety and biocompatibility of the material, thereby improving dental care.

Super-Linear-Threshold-Switching Selector with Multiple Jar-Shaped Cu-Filaments in the Amorphous Ge3 Se7 Resistive Switching Layer in a Cross-Point Synaptic Memristor Array.

The learning and inference efficiencies of an artificial neural network represented by a cross-point synaptic memristor array can be achieved using a selector, with high selectivity (Ion /Ioff ) and sufficient death region, stacked vertically on a synaptic memristor. This can prevent a sneak current in the memristor array. A selector with multiple jar-shaped conductive Cu filaments in the resistive switching layer is precisely fabricated by designing the Cu ion concentration depth profile of the CuGeSe layer as a filament source, TiN diffusion barrier layer, and Ge3 Se7 switching layer. The selector performs super-linear-threshold-switching with a selectivity of > 107 , death region of -0.70-0.65 V, holding time of 300 ns, switching speed of 25 ns, and endurance cycle of > 106 . In addition, the mechanism of switching is proven by the formation of conductive Cu filaments between the CuGeSe and Ge3 Se7 layers under a positive bias on the top Pt electrode and an automatic rupture of the filaments after the holding time. Particularly, a spiking deep neural network using the designed one-selector-one-memory cross-point array improves the Modified National Institute of Standards and Technology classification accuracy by ≈3.8% by eliminating the sneak current in the cross-point array during the inference process.

Lactobacillus plantarum Lipoteichoic Acids Possess Strain-Specific Regulatory Effects on the Biofilm Formation of Dental Pathogenic Bacteria.

Bacterial biofilm residing in the oral cavity is closely related to the initiation and persistence of various dental diseases. Previously, we reported the anti-biofilm activity of Lactobacillus plantarum lipoteichoic acid (Lp.LTA) on a representative dental cariogenic pathogen, Streptococcus mutans. Since LTA structure varies in a bacterial strain-specific manner, LTAs from various L. plantarum strains may have differential anti-biofilm activity due to their distinct molecular structures. In the present study, we isolated Lp.LTAs from four different strains of L. plantarum (LRCC 5193, 5194, 5195, and 5310) and compared their anti-biofilm effects on the dental pathogens, including S. mutans, Enterococcus faecalis, and Streptococcus gordonii. All Lp.LTAs similarly inhibited E. faecalis biofilm formation in a dose-dependent manner. However, their effects on S. gordonii and S. mutans biofilm formation were different: LRCC 5310 Lp.LTA most effectively suppressed the biofilm formation of all strains of dental pathogens, while Lp.LTAs from LRCC 5193 and 5194 hardly inhibited or even enhanced the biofilm formation. Furthermore, LRCC 5310 Lp.LTA dramatically reduced the biofilm formation of the dental pathogens on the human dentin slice infection model. Collectively, these results suggest that Lp.LTAs have strain-specific regulatory effects on biofilm formation of dental pathogens and LRCC 5310 Lp.LTA can be used as an effective anti-biofilm agent for the prevention of dental infectious diseases.

Regulation of Bone Cell Differentiation and Activation by Microbe-Associated Molecular Patterns.

Gut microbiota has emerged as an important regulator of bone homeostasis. In particular, the modulation of innate immunity and bone homeostasis is mediated through the interaction between microbe-associated molecular patterns (MAMPs) and the host pattern recognition receptors including Toll-like receptors and nucleotide-binding oligomerization domains. Pathogenic bacteria such as Porphyromonas gingivalis and Staphylococcus aureus tend to induce bone destruction and cause various inflammatory bone diseases including periodontal diseases, osteomyelitis, and septic arthritis. On the other hand, probiotic bacteria such as Lactobacillus and Bifidobacterium species can prevent bone loss. In addition, bacterial metabolites and various secretory molecules such as short chain fatty acids and cyclic nucleotides can also affect bone homeostasis. This review focuses on the regulation of osteoclast and osteoblast by MAMPs including cell wall components and secretory microbial molecules under in vitro and in vivo conditions. MAMPs could be used as potential molecular targets for treating bone-related diseases such as osteoporosis and periodontal diseases.

Bacterial Lipoproteins Induce BAFF Production via TLR2/MyD88/JNK Signaling Pathways in Dendritic Cells.

B-cell activating factor (BAFF) plays a crucial role in survival, differentiation, and antibody secretion of B cells. Microbial products with B-cell mitogenic properties can indirectly promote expansion and activation of B cells by stimulating accessory cells, such as dendritic cells (DCs), to induce BAFF. Although bacterial lipoproteins are potent B-cell mitogen like lipopolysaccharides (LPSs), it is uncertain whether they can stimulate DCs to induce BAFF expression. Here, we evaluated the effect of bacterial lipoproteins on BAFF expression in mouse bone marrow-derived DCs. Lipoprotein-deficient Staphylococcus aureus mutant induced relatively low expression level of membrane-bound BAFF (mBAFF) and the mRNA compared with its wild-type strain, implying that bacterial lipoproteins can positively regulate BAFF induction. The synthetic lipopeptides Pam2CSK4 and Pam3CSK4, which mimic bacterial lipoproteins, dose-dependently induced BAFF expression, and their BAFF-inducing capacities were comparable to those of LPS in DCs. Induction of BAFF by the lipopeptide was higher than the induction by other microbe-associated molecular patterns, including peptidoglycan, flagellin, zymosan, lipoteichoic acid, and poly(I:C). Pam3CSK4 induced both mBAFF and soluble BAFF expression in a dose- and time-dependent manner. BAFF expression by Pam3CSK4 was completely absent in DCs from TLR2- or MyD88-deficient mice. Among various MAP kinase inhibitors, only JNK inhibitors blocked Pam3CSK4-induced BAFF mRNA expression, while inhibitors blocking ERK or p38 kinase had no such effect. Furthermore, Pam3CSK4 increased the DNA-binding activities of NF-κB and Sp1, but not that of C/EBP. Pam3CSK4-induced BAFF promoter activity via TLR2/1 was blocked by NF-κB or Sp1 inhibitor. Collectively, these results suggest that bacterial lipoproteins induce expression of BAFF through TLR2/MyD88/JNK signaling pathways leading to NF-κB and Sp1 activation in DCs, and BAFF derived from bacterial lipoprotein-stimulated DCs induces B-cell proliferation.

Clinical and electrocardiographic characteristics for prediction of new-onset atrial fibrillation in asymptomatic patients with atrial premature complexes.

BACKGROUNDS: Identification of precursors of atrial fibrillation (AF) may lead to early detection and prevent associated morbidity and mortality. Atrial premature complexes (APCs) are commonly seen in healthy subjects. However, there was limited data about the clinical and electrocardiographic (ECG) characteristics for prediction of new-onset AF in asymptomatic patients with APCs in the long-term follow up. METHODS: The Kosin University (No. 2014-02-04) 24-h holter monitoring, echocardiography, ECG database were reviewed from 2008 to 2016 to identify new- onset AF in patients with APCs. We analyzed demographic and clinical features and the nature of the APCs by ECG according to new-onset AF in those patients. RESULTS: Among 652 patients who underwent 24-h holter monitoring, 226 (34.4%) patients had new-onset AF. There was no difference of the baseline characteristics between new-onset AF group and non-AF group. In univariate analysis, hypertension (HTN), renal failure (CRF), high APC burdens, fastest APC running heart rate (HR), minimal HR, left ventricular ejection fraction (LVEF), left atrial volume index, peak mitral flow velocity of the early rapid filling wave and tricuspid regurgitation grade were significantly associated with new-onset AF. In multivariate analysis, higher APCs burden (P = 0.047), higher fastest APCs running HR (P = 0.034) and lower minimal HR (P = 0.025) were independent risk factors for new-onset AF in asymptomatic patients with APCs. CONCLUSION: Higher APCs burden, higher fastest APCs running HR and lower minimal HR were associated with new-onset AF in asymptomatic patients with APCs in the long-term follow up.

Flexible Memristive Devices Based on InP/ZnSe/ZnS Core-Multishell Quantum Dot Nanocomposites.

The effects of the ZnS shell layer on the memory performances of flexible memristive devices based on quantum dots (QDs) with an InP/ZnSe/ZnS core-multishell structure embedded in a poly(methylmethacrylate) layer were investigated. The on/off ratios of the devices based on QDs with an InP/ZnSe core-shell structure and with an InP/ZnSe/ZnS core-multishell structure were approximately 4.2 × 102 and 8.5 × 103, respectively, indicative of enhanced charge storage capability in the latter. After bending, the memory characteristics of the memristive devices based on QDs with the InP/ZnSe/ZnS structure were similar to those before bending. In addition, those devices maintained the same on/off ratios for retention time of 1 × 104 s, and the number of endurance cycles was above 1 × 102. The reset voltages ranged from -2.3 to -3.1 V, and the set voltages ranged from 1.3 to 2.1 V, indicative of reliable electrical characteristics. Furthermore, the possible operating mechanisms of the devices are presented on the basis of the electron trapping and release mode.

Association between right ventricular systolic function and electromechanical delay in patients with right bundle branch block.

BACKGROUND: Elevated right ventricle (RV) pressure and/or volume can place stress on the right bundle branch block (RBBB) and its associated Purkinje network, which can affect its electrical properties, resulting in conduction delay or block. We hypothesized that prolonged R' wave duration in lead V1 would extend the later portion of the QRS complex and can act as an indicator of reduced RV function in patients with RBBB. METHOD: Kosin University Gospel Hospital echocardiography and electrocardiography (ECG) database was reviewed to identify patients with complete RBBB between 2013 and 2015. ECGs recorded closest to the time of the echocardiography were carefully reviewed, and QRS and R' wave duration were measured. RV systolic dysfunction was defined as an RV fractional area change (FAC) less than 35%, as indicated by echocardiography guidelines. RESULTS: Compared to patients with normal RV function (n=241), patients with RV dysfunction (n=123) showed prolonged QRS duration (145.3±19.3ms vs. 132.2±13.4ms, p<0.001), predominantly due to R' prolongation (84.8±13.0ms vs. 102.9±12.0ms, p<0.001). R' duration was significantly associated with RV FAC (r=-0.609, p<0.001), RV systolic pressure (r=0.142, p=0.008), RV dimension (r=0.193, p<0.001), and RV myocardial performance index (r=0.199, p<0.001). On receiving operator characteristic curve analysis, V1 R' duration ≥93ms was associated with RV dysfunction with 90% sensitivity and 87% specificity (area under the curve: 0.883, 95% confidence interval=0.845-0.914, p<0.001). CONCLUSION: Prolonged R' wave duration in lead V1 is an indicator of RV dysfunction and pressure and/or volume overload in patients with RBBB.

Epicardial Fat Thickness and Neutrophil to Lymphocyte Ratio are Increased in Non-Dipper Hypertensive Patients.

BACKGROUND: In this study, we aimed to investigate the relationship between echocardiographic epicardial fat thickness (EFT), neutrophil to lymphocyte ratio (NLR; an important inflammatory marker), and diurnal blood pressure (BP) changes in patients with recently diagnosed essential hypertension. METHODS: A total of 647 patients underwent echocardiography and 24 hours of ambulatory BP monitoring. EFT was measured by echocardiography, while NLR was measured by dividing the neutrophil count by the lymphocyte count. Patients were categorized into three groups according to BP pattern: the normotensive group, the dipper group, and the non-dipper group. RESULTS: The mean EFT was highest in the non-dipper group (non-dipper group, 7.3 ± 3.0 mm; dipper group, 6.1 ± 2.0 mm; control group, 5.6 ± 2.0 mm; p < 0.001). NLR was also highest in the non-dipper group (non-dipper, 2.75 ± 2.81; dipper, 2.01 ± 1.32; control, 1.92 ± 1.11; p < 0.001). EFT was significantly correlated with age (r = 0.160, p < 0.001) and NLR (r = 0.353, p < 0.001). Furthermore, an EFT ≥ 7.0 mm was associated with the non-dipper BP pattern with 51.3% sensitivity and 71.6% specificity [95% confidence interval (CI) = 0.56-0.65, p < 0.001]. In a multivariate analysis, EFT [adjusted odds ratio (OR) = 3.99, 95% CI = 1.22-13.10, p = 0.022] and NLR (OR = 1.34, 95% CI = 1.05-1.71, p = 0.018) were independent parameters that distinguished a non-dipper pattern after adjustment for cardiovascular risk factors. CONCLUSION: EFT and NLR are independently associated with impaired diurnal BP profiles in hypertensive individuals. EFT (as measured by echocardiography) and NLR appear to be helpful in stratifying cardiometabolic risk.

Anti-cancer effect of tectochrysin in NSCLC cells through overexpression of death receptor and inactivation of STAT3.

Phenolic compounds (flavonoids and phenolic acid derivatives) are the most important pharmacologically active ingredients, and these compounds could inhibit proliferation of human cancer cells by inducing of apoptotic cell death. Here we focused on the anticancer effects of tectochrysin on human non-small-cell lung cancer (NSCLC) cells and its mechanism of action. We analysed the activity of tectochrysin on NSCLC cells (A549 and NCI-H460) by use of Western blot analysis for major apoptotic proteins and death receptor expression. We also used EMSA for effects on STAT3 DNA binding activity. Tectochrysin (0-80 µM) suppressed the growth of A549 and NCI-H460 lung cancer cells by inducing of apoptotic cell death in a concentration dependent manner. Expression of DR3 and Fas as well as DR downstream pro-apoptotic proteins including cleaved caspase-3, cleaved caspase-8, cleaved caspase-9 and Bax were concomitantly increased, but the expression of anti-apoptotic proteins; Bcl-2 was decreased in both cancer cells. In addition, tectochrysin treatment also inhibited phosphorylation of STAT3 in A549 and NCI-H460 cells. However, deletion of DR3 and Fas by small interfering RNA significantly reversed tectochrysin-induced cell growth inhibitory effect as well as down regulation of STAT3 in A549 and NCI-H460 lung cancer cells. Pull down assay and docking model showed interaction of tectochrysin with STAT3. We propose that tectochrysin leads to apoptotic cell death in NSCLC cells through activation of DR3 and Fas expression via inhibition of STAT3 phosphorylation.

Synthesis of aminoalkyl-substituted coumarin derivatives as acetylcholinesterase inhibitors.

Alzheimer's disease, one of the most common forms of dementia, is a progressive neurodegenerative disorder symptomatically characterized by declines in memory and cognitive abilities. To date, the successful therapeutic strategy to treat AD is maintaining levels of acetylcholine by inhibiting acetylcholinesterase (AChE). In the present study, coumarin derivatives were designed and synthesized as AChE inhibitors based on the lead structure of scopoletin. Of those synthesized, pyrrolidine-substituted coumarins 3b and 3f showed ca. 160-fold higher AChE inhibitory activities than scopoletin. These compounds also ameliorated scopolamine-induced memory deficit in mice when administered orally at the dose of 1 and 2 mg/kg.

An ethanolic extract of Lindera obtusiloba stems, YJP-14, improves endothelial dysfunction, metabolic parameters and physical performance in diabetic db/db mice.

Lindera obtusiloba is a medicinal herb traditionally used in Asia for improvement of blood circulation, treatment of inflammation, and prevention of liver damage. A previous study has shown that an ethanolic extract of Lindera obtusiloba stems (LOE) has vasoprotective and antihypertensive effects. The possibility that Lindera obtusiloba improves endothelial function and metabolic parameters in type 2 diabetes mellitus (T2DM) remains to be examined. Therefore, the aim of the present study was to determine the potential of LOE to prevent the development of an endothelial dysfunction, and improve metabolic parameters including hyperglycemia, albuminuria and physical exercise capacity in db/db mice, an experimental model of T2DM. The effect of LOE (100 mg/kg/day by gavage for 8 weeks) on these parameters was compared to that of an oral antidiabetic drug, pioglitazone (30 mg/kg/day by gavage). Reduced blood glucose level, body weight and albumin-creatinine ratio were observed in the group receiving LOE compared to the control db/db group. The LOE treatment improved endothelium-dependent relaxations, abolished endothelium-dependent contractions to acetylcholine in the aorta, and normalized the increased vascular oxidative stress and expression of NADPH oxidase, cyclooxygenases, angiotensin II, angiotensin type 1 receptors and peroxynitrite and the decreased expression of endothelial NO synthase in db/db mice. The angiotensin-converting enzyme (ACE) activity was reduced in the LOE group compared to that in the control db/db group. LOE also inhibited the activity of purified ACE, COX-1 and COX-2 in a dose-dependent manner. In addition, LOE improved physical exercise capacity. Thus, the present findings indicate that LOE has a beneficial effect on the vascular system in db/db mice by improving endothelium-dependent relaxations and vascular oxidative stress most likely by normalizing the angiotensin system, and also on metabolic parameters, and these effects are associated with an enhanced physical exercise capacity.

An ethanolic extract of Lindera obtusiloba stems causes NO-mediated endothelium-dependent relaxations in rat aortic rings and prevents angiotensin II-induced hypertension and endothelial dysfunction in rats.

Lindera obtusiloba is a medical herb traditionally used in Asia for the improvement of blood circulation, treatment of inflammation, and prevention of liver damage. The possibility that L. obtusiloba affects vascular reactivity remains to be examined. Therefore, the aim of the present study was to evaluate both the in vitro and in vivo vascular effects of an ethanolic extract of L. obtusiloba stems (LOE). Vascular reactivity was assessed in organ chambers using rat aortic rings and the activation of endothelial NO synthase (eNOS) in cultured bovine aortic endothelial cells. LOE induced endothelium-dependent relaxations, which were abolished by inhibitors of nitric oxide synthase (N (ω)-nitro-L: -arginine) and guanylyl cyclase (1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-L-one), significantly reduced by inhibitors of PI3 kinase (wortmannin and LY294002), and not affected by inhibitors of cyclooxygenase (indomethacin) and endothelium-derived hyperpolarizing factor-mediated responses (charybdotoxin plus apamin). LOE prevented contractile responses to phenylephrine and angiotensin II in rings with endothelium, but not in those without endothelium. LOE caused a concentration-dependent phosphorylation of Akt at Serine473 and eNOS at Serine1177 in endothelial cells. Thereafter, the vasoprotective effect of LOE was investigated in an experimental model of hypertension in rats. Intake of LOE prevented the angiotensin II-induced increase in systolic blood pressure, and endothelial dysfunction to acetylcholine and oxidative stress as assessed using dihydroethidine in aortic rings. The present findings indicate that LOE has vasoprotective and antihypertensive properties most likely by stimulating the endothelial formation of NO and inhibiting oxidative stress.

The n-butanolic extract of Opuntia ficus-indica var. saboten enhances long-term memory in the passive avoidance task in mice.

Opuntia ficus-indica var. saboten Makino (Cactaceae) is used to treat burns, edema, dyspepsia, and asthma in traditional medicine. The present study investigated the beneficial effects of the n-butanolic extract of O. ficus-indica var. saboten (BOF) on memory performance in mice and attempts to uncover the mechanisms underlying its action. Memory performance was assessed with the passive avoidance task, and western blotting and immunohistochemistry were used to measure changes in protein expression and cell survival. After the oral administration of BOF for 7 days, the latency time in the passive avoidance task was significantly increased relative to vehicle-treated controls (P<0.05). Western blotting revealed that the expression levels of brain-derived neurotrophic factor (BDNF), phosphorylated cAMP response element binding-protein (pCREB), and phosphorylated extracellular signal-regulated kinase (pERK) 1/2 were significantly increased in hippocampal tissue after 7 days of BOF administration (P<0.05). Doublecortin and 5-bromo-2-deoxyuridine immunostaining also revealed that BOF significantly enhanced the survival of immature neurons, but did not affect neuronal cell proliferation in the subgranular zone of the hippocampal dentate gyrus. These results suggest that the subchronic administration of BOF enhances long-term memory, and that this effect is partially mediated by ERK-CREB-BDNF signaling and the survival of immature neurons.

Quercetin impairs learning and memory in normal mice via suppression of hippocampal phosphorylated cyclic AMP response element-binding protein expression.

Quercetin is a naturally occurring dietary flavonol and several reports have shown that quercetin substantially affects cognitive function in disease models, which suggests that quercetin might be a useful agent for treatment of memory dysfunction. However, only one report has examined the effects of quercetin on normal cognitive function. In the present study, we investigated the potential deleterious effects of quercetin on normal cognitive function using Western blot assays and the following behavioral tasks: passive avoidance, Y-maze, and Morris water maze. In the passive avoidance task, pre-acquisition administration of quercetin (10, 20, or 40 mg/kg, p.o.) caused significant cognitive impairments in mice (P < 0.05 or P < 0.01). Quercetin-treated groups (10, 20, or 40 mg/kg, p.o.) also showed significant memory impairments compared with the control group in the Y-maze task (P < 0.05). In the Morris water maze task, there were no significant differences among the groups during training trial sessions, but at the probe trial session, the quercetin-treated group (40 mg/kg, p.o.) spent significantly less time in the target quadrant than did the control group (P < 0.05). In Western blot assays of hippocampal tissue, we found that quercetin-treated groups showed decreased expression of phosphorylated Akt (pAkt), phosphorylated calcium-calmodulin kinase II (pCaMKII), and phosphorylated cyclic AMP response element-binding protein (pCREB). These results suggest that acute administration of quercetin impairs cognitive function by suppression of pAkt and pCaMKII, which, in turn, decreases pCREB expression in the hippocampus.

The ameliorating effect of the extract of the flower of Prunella vulgaris var. lilacina on drug-induced memory impairments in mice.

Prunella vulgaris var. lilacina is widely distributed in Korea, Japan, China, and Europe, and its flowers are used to treat inflammation in traditional Chinese medicine. In the present study, we studied the effects of the ethanolic extract of the flower of P. vulgaris var. lilacina (EEPV) on drug-induced learning and memory impairment using the passive avoidance, the Y-maze, and the Morris water maze tasks in mice. EEPV (25 or 50 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, EEPV (25 mg/kg, p.o.) significantly shortened escape latencies in training-trials. Furthermore, swimming times within the target zone during the probe-trial were significantly increased as compared with scopolamine-treated mice (P<0.05). In addition, the reduced latency induced by MK-801 treatment in the passive avoidance task was ameliorated by EEPV (25 mg/kg, p.o.) (P<0.05). Additionally, the ameliorating effect of EEPV on scopolamine-induced memory dysfunction was antagonized by a sub-effective dose of MK-801. These results suggest that EEPV would be useful for treating cognitive impairments induced by cholinergic dysfunction, and that it exerts its effects via NMDA receptor signaling.

Sinapic acid attenuates kainic acid-induced hippocampal neuronal damage in mice.

Excitotoxin induces neurodegeneration via glutamatergic activation or oxidative stress, which means that the blockade of glutamate receptors and the scavenging of free radicals are potential therapeutic targets in neurodegenerative diseases. Sinapic acid (SA) has a GABA(A) receptor agonistic property and free radical scavenging activity. We investigated the neuroprotective effects of SA on kainic acid (KA)-induced hippocampal brain damage in mice. SA (10 mg/kg) by oral administration has an anticonvulsant effect on KA-induced seizure-like behavior. Moreover, SA (10 mg/kg) significantly attenuated KA-induced neuronal cell death in the CA1 and CA3 hippocampal regions when administered as late as 6 h after KA. In addition, flumazenil, a GABA(A) antagonist, blocked the effect of SA administered immediately after KA but not the effect of SA administered 6 h after KA. This late protective effect of SA was accompanied by reduced levels of reactive gliosis, inducible nitric oxide synthase expression, and nitrotyrosine formation in the hippocampus. In the passive avoidance task, KA-induced memory impairments were ameliorated by SA. These results suggest that the potential therapeutic effect of SA is due to its attenuation of KA-induced neuronal damage in the brain via its anti-convulsive activity through GABA(A) receptor activation and radical scavenging activity.

Subchronic administration of rosmarinic acid, a natural prolyl oligopeptidase inhibitor, enhances cognitive performances.

It is well known that inhibition of prolyl oligopeptidase (POP) is involved in memory-related function. In this study, we observed that rosmarinic acid (RA) inhibits POP activity with an IC(50) of 63.7 microM. Subsequently, we investigated the cognitive-enhancing effects of RA employing the Morris water maze paradigm. The results demonstrated that RA is non-competitive POP inhibitor and that acute and subchronic RA treatments showed an inverted U-shaped dose-response curve in the platform crossings. Furthermore, chronic RA treatment significantly increased the platform crossings. These results suggest that RA has a cognitive-enhancing effect which may be mediated by inhibition of POP.

The memory-enhancing effects of Euphoria longan fruit extract in mice.

AIM OF THE STUDY: The fruit of Euphoria longan (Lour.) Steud. (Sapindaceae) is sweet and edible. Dried Euphoria longan fruit is prescribed as a tonic and for the treatment of forgetfulness, insomnia, or palpitations caused by fright in traditional Chinese medicine. The effects of aqueous extract of Euphoria longan fruit (ELE) on learning and memory and their underlying mechanisms were investigated. MATERIALS AND METHODS: Aqueous extract of Euphoria longan fruit (ELE) was administered to ICR mice for 14 days. Piracetam was used as a positive control for its known memory-enhancing effects. Memory performances were assessed using the passive avoidance task. The expressions of phosphorylated extracellular signal-regulated kinase (pERK) 1/2, phosphorylated cAMP response element binding protein (pCREB), brain-derived neurotrophic factor (BDNF), doublecortin (DCX) and the incorporation of 5-bromo-2-deoxyuridine (BrdU) in hippocampal dentate gyrus and CA1 regions were investigated using immunohistochemical methods. RESULTS: The step-through latency in the ELE-treated group was significantly increased compared with that in the vehicle-treated controls (P<0.05) in the passive avoidance task. Piracetam-treated group also showed enhanced cognitive performaces in the passive avoidance task. Immunohistochemical studies revealed that the number of cells immunopositive for BDNF, pCREB, or pERK 1/2 was significantly increased in the hippocampal dentate gyrus and CA1 regions after ELE treatment for 14 days (P<0.05). DCX and BrdU immunostaining also revealed that ELE significantly enhanced immature neuronal survival, but not neuronal cell proliferation in the subgranular zone of the dentate gyrus. CONCLUSIONS: The present results suggest that subchronic administration of aqueous extract of Euphoria longan fruit enhances learning and memory, and that its beneficial effects are mediated, in part, by BDNF expression and immature neuronal survival.