Uvaol ameliorates lipid deposition in hyperlipidemic hepatocytes by suppressing protein-tyrosine phosphatase 1B/ER stress signaling.

Uvaol (UV), a pentacyclic triterpene found in olives and virgin olive oil, is known for its anti-inflammatory and antioxidant effects in various disease models. While olive oil is reported to reduce obesity and insulin resistance, the specific impact of UV on liver lipid metabolism and its molecular mechanisms are not fully understood. In this study, hepatic lipid accumulation was measured using oil red O staining, and protein expression levels in liver cells were assessed via Western blot analysis. Apoptosis was evaluated through cell viability and caspase 3 activity assays. UV treatment reduced lipid accumulation, fatty acid uptake, apoptosis, and ER stress in palmitate-treated liver cells. Additionally, UV enhanced fatty acid oxidation. Mechanistically, increased SIRT6 expression and autophagy were observed in UV-treated cells. SIRT6-targeted siRNA or 3-methyladenine blocked the effects of UV in hyperlipidemic cells. In conclusion, UV improves SIRT6/autophagy signaling, reducing lipid deposition and apoptosis in liver cells under high lipid conditions. This in vitro study provides strong evidence for potential therapeutic strategies for hepatic steatosis.

The Distribution of the Nerves and Arteries of the Platysma for Clinical Applications.

This study aimed to provide anatomical data on the platysma for clinical procedures. The authors obtained 25 specimens from 15 adult Korean cadavers (9 men, 6 women; mean age, 72 years; range, 61-85 years). Lines connecting the gonion with the gnathion (G-GN) and the acromial end (acromial end of the clavicle) with the sternal end (sternal end of the clavicle) were used as references. Modified Sihler staining was used to trace the nerves distributed in the platysma. The superior border values of the platysma were 12.1 ± 2.7 mm, 31.5 ± 5.3 mm, 42.4 ± 5.6 mm, and 61.7 ± 6.4 mm, respectively, for sections 2 through 5 on the G-GN line. The inferior border values of the platysma were 83.6 ± 19.1 mm, 80.1 ± 14.0 mm, 74.8 ± 14.5 mm, 67.2 ± 13.7 mm, and 54.6 ± 7.1 mm, respectively, for the 5 sections on the acromial end of the clavicle-sternal end of the clavicle line. In the hyoid bone, cricoid cartilage, and jugular notch, the mean distance between the bilateral platysma was 14.4 ± 2.2 mm, 22.6 ± 10.6 mm, and 51.1 ± 15.7 mm, respectively. The mean angle at the cervical branch of the facial nerve and the anterior border of the sternocleidomastoid muscle sternal head was 28.7 ± 2.6 degrees and 53.4 ± 7.7 degrees from the G-GN line, respectively. The upper third of the platysma was supplied by branches of the facial artery and submental artery. The middle third was supplied by branches of the occipital artery and received its direct blood supply from branches of the external carotid artery. The lower third was supplied by branches of the transverse cervical artery. The authors hope that the results of this study will be helpful for rejuvenation procedures of the neck.

Ginsenoside Re Protects against Serotonergic Behaviors Evoked by 2,5-Dimethoxy-4-iodo-amphetamine in Mice via Inhibition of PKCδ-Mediated Mitochondrial Dysfunction.

It has been recognized that serotonin 2A receptor (5-HT2A) agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI) impairs serotonergic homeostasis. However, the mechanism of DOI-induced serotonergic behaviors remains to be explored. Moreover, little is known about therapeutic interventions against serotonin syndrome, although evidence suggests that ginseng might possess modulating effects on the serotonin system. As ginsenoside Re (GRe) is well-known as a novel antioxidant in the nervous system, we investigated whether GRe modulates 5-HT2A receptor agonist DOI-induced serotonin impairments. We proposed that protein kinase Cδ (PKCδ) mediates serotonergic impairments. Treatment with GRe or 5-HT2A receptor antagonist MDL11939 significantly attenuated DOI-induced serotonergic behaviors (i.e., overall serotonergic syndrome behaviors, head twitch response, hyperthermia) by inhibiting mitochondrial translocation of PKCδ, reducing mitochondrial glutathione peroxidase activity, mitochondrial dysfunction, and mitochondrial oxidative stress in wild-type mice. These attenuations were in line with those observed upon PKCδ inhibition (i.e., pharmacologic inhibitor rottlerin or PKCδ knockout mice). Furthermore, GRe was not further implicated in attenuation mediated by PKCδ knockout in mice. Our results suggest that PKCδ is a therapeutic target for GRe against serotonergic behaviors induced by DOI.

1,2-Dilinoleoyl-sn-glycero-3-phosphocholine increases insulin sensitivity in palmitate-treated myotubes and induces lipolysis in adipocytes.

Obesity causes the development of insulin resistance and type 2 diabetes. Phosphatidylcholine (PPC) has been reported to increase hepatic insulin sensitivity and lipolysis in adipose tissue to resolve local obesity. In this study, we proposed 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), the main active species of PPC, as an effective substance for the treatment of obesity-mediated disorders such as impaired fat metabolism and insulin resistance. Therefore, we investigated the potential lipolytic effects of DLPC on adipocytes and insulin signaling in muscle cells. In this study, DLPC-treated 3T3-L1 adipocytes showed enhanced tumor necrosis factor α (TNF-α) release. Suppression of TNF-α by short interfering RNA (siRNA) mitigated DLPC-induced lipolysis and apoptosis. DLPC treatment increased peroxisome proliferator-activated receptor α (PPARα) expression levels in C2C12 myocytes. siRNA-mediated suppression of PPARα abrogated the suppressive effects of DLPC on palmitate-induced inflammation and insulin resistance. In conclusion, DLPC enhanced lipolysis and apoptosis via a TNFα-dependent pathway in adipocytes and attenuated palmitate-induced insulin resistance through PPARα-mediated suppression of inflammation in myocytes.

Glutathione Peroxidase-1 Knockout Facilitates Memory Impairment Induced by ß-Amyloid (1-42) in Mice via Inhibition of PKC ßII-Mediated ERK Signaling; Application with Glutathione Peroxidase-1 Gene-Encoded Adenovirus Vector.

A growing body evidence suggests that selenium (Se) deficiency is associated with an increased risk of developing Alzheimer's disease (AD). Se-dependent glutathione peroxidase-1 (GPx-1) of a major antioxidant enzyme, and the most abundant isoform of GPx in the brain. In the present study, we investigated whether GPx-1 is protective against memory impairments induced by beta-amyloid (Aß) (1-42) in mice. As the alteration of protein kinase C (PKC)-mediated ERK activation was recognized in the early stage of AD, we examined whether the GPx-1 gene modulates Aß (1-42)-induced changes in PKC and ERK levels. We observed that Aß (1-42) treatment (400 pmol, i.c.v.) significantly decreased PKC ßII expression in the hippocampus of mice. Aß (1-42)-induced neurotoxic changes [i.e., oxidative stress (i.e., reactive oxygen species, 4-hydroxy-2-noneal, and protein carbonyl), reduced PKC ßII and phospho-ERK expressions, and memory impairment under Y-maze and passive avoidance test] were more pronounced in GPx-1 knockout than in wild type mice. Importantly, exposure to a GPx-1 gene-encoded adenovirus vector (Adv-GPx-1) significantly increased GPx-1 mRNA and GPx activity in the hippocampus of GPx-1 knockout mice. Adv-GPx-1 exposure also significantly blocked the neurotoxic changes induced by Aß (1-42) in GPx-1 knockout mice. Treatment with ERK inhibitor U0126 did not significantly change Adv-GPx-1-mediated attenuation in PKC ßII expression. In contrast, treatment with PKC inhibitor chelerythrine (CHE) reversed Adv-GPx-1-mediated attenuation in ERK phosphorylation, suggesting that PKC ßII-mediated ERK signaling is important for Adv-GPx-1-mediated potentials against Aß (1-42) insult. Our results suggest that treatment with the antioxidant gene GPx-1 rescues Aß (1-42)-induced memory impairment via activating PKC ßII-mediated ERK signaling.

Glutathione peroxidase-1 gene rescues cocaine-induced conditioned place preference in mice by inhibiting σ-1 receptor expression.

The aim of this study was to investigate whether the glutathione peroxidase-1 gene (GPx-1) affects cocaine-induced conditioned place preference (CPP) using a mouse model. Cocaine-induced CPP was accompanied by an increase in the level of σ-1 receptor in the nucleus accumbens (NAc). This phenomenon was more pronounced in the GPx-1 gene knockout (GPx-1 KO) than in wild type (WT) mice. In contrast, the CPP and expression of σ-1 receptor were much less pronounced in GPx-1-overexpressing transgenic (GPx-1 TG) mice than non-transgenic (non-TG) mice. Treatment of the mice with BD1047, a σ-1 receptor antagonist, significantly attenuated both cocaine-induced CPP and c-Fos-immunoreactivity (c-Fos-IR) in WT and GPx-1 KO mice, although the effects were more evident in the latter group. Despite the protective effects of BD1047 on cocaine-induced CPP and c-Fos in non-TG mice, there were no additional protective effects in cocaine-treated GPx-1 TG mice, indicating that the σ-1 receptor is a critical target for GPx-1-mediated psychoprotective activity. Overall, our results suggest that GPx-1 attenuates cocaine-induced CPP via inhibition of σ-1 receptor expression.

Protectin DX attenuates LPS-induced inflammation and insulin resistance in adipocytes via AMPK-mediated suppression of the NF-κB pathway.

Several studies have demonstrated that protectins, ω-3 fatty acid-derived proresolution mediators, may ameliorate inflammation. Recently, protectin DX (PDX) was also reported to attenuate inflammation and insulin resistance in several cell types. However, the effects of PDX on inflammation in adipocytes remain ambiguous. In this study, we found that PDX treatment suppressed adipogenesis and lipid accumulation during 3T3-L1 differentiation. Treatment of differentiated 3T3-L1 cells with PDX stimulated AMP-activated protein kinase (AMPK) phosphorylation in a dose-dependent manner. PDX-induced AMPK phosphorylation blocked lipopolysaccharide (LPS)-induced secretion of proinflammatory cytokines, such as tumor necrosis factor-α and monocyte chemoattractant protein-1. Treatment of 3T3-L1 cells with PDX alleviated LPS-induced NF-κB and inhibitory factor κB phosphorylation. Furthermore, PDX treatment diminished LPS-induced impairment of insulin signaling and insulin-stimulated glucose uptake, as well as fatty acid oxidation. These effects were decreased by silencing AMPK expression with small-interfering RNA. In conclusion, the current findings suggest that PDX attenuates inflammation and insulin resistance in adipocytes via an AMPK-dependent pathway, which in turn provides evidence that PDX has anti-inflammatory and antidiabetic effects in adipocytes.

p-Coumaric acid stimulates longitudinal bone growth through increasing the serum production and expression levels of insulin-like growth factor 1 in rats.

The aim of the present study was to examine the effects of p-coumaric acid on the longitudinal growth of the long bone in adolescent male rats. Teatment with p-coumaric acid significantly increased the tibial length and the height of each growth plate zone and the ratio of 5-bromo-2'-deoxyuridine-positive cells relative to total proliferative cells. Expression of insulin-like growth factor 1 and its receptor in the proliferative and hypertrophic zones, and serum levels of growth hormone and insulin-like growth factor 1 were significantly increased as well in the p-coumaric acid-treated group. Via increasing both the serum level of insulin-like growth factor 1 and its expression, p-coumaric acid could promote cell proliferation in growth plate zones. These results suggest that p-coumaric acid has the potential to increase height and may be a feasible alternative to growth hormone therapy.

Phosphatidylcholine Causes Lipolysis and Apoptosis in Adipocytes through the Tumor Necrosis Factor Alpha-Dependent Pathway.

A phosphatidylcholine (PPC) formulation has been used to treat cellulite; however, its underlying mechanism of action remains unclear. In this study, we demonstrated that PPC induces lipolysis and apoptosis in adipocytes, and evaluated a possible tumor necrosis factor alpha (TNFα)-dependent pathway, whereby PPC exerts these effects. For in vitro study, fully differentiated 3T3-L1 cells, mouse adipocytes were treated with various concentrations of PPC and cell apoptosis and lipolysis were assayed. For in vivo experiments, mice fed on a high-fat diet for 8 weeks were injected twice to abdominal subcutaneous fat tissues of either vehicle or PPC. We found that PPC induced lipolysis and apoptosis dose-dependently in fully differentiated 3T3-L1 cells. In addition, PPC augmented both expression and release of TNFα in a dose-dependent fashion. Induction of TNFα by PPC was associated with the stimulation of nuclear factor kappa B (NFκB)-mediated transcriptional activity. Small interfering RNA (siRNA)-mediated suppression of NFκB abrogated the effect of PPC on TNFα secretion. Suppression of TNFα with specific siRNA abrogated the effects of PPC on lipolysis and apoptosis. Through in vivo experiments, we demonstrated that PPC injection not only stimulated the local lipolysis and apoptosis, resulting in weight loss, but also induced TNFα mRNA expression and neutrophil infiltration. Furthermore, PPC injection prevented lipogenesis and suppressed the mRNA -expression of adipokines (such as adiponectin and leptin), due to the down-sizing of adipocytes. In conclusion, we suggest that PPC induces lipolysis and apoptosis in adipocytes through TNFα-dependent pathways.

Protective potential of glutathione peroxidase-1 gene against cocaine-induced acute hepatotoxic consequences in mice.

Since the cocaine-induced oxidative stress has been established to lead to hepatotoxicity, we examined the role of the glutathione peroxidase (GPx)-1 gene in cocaine-induced hepatotoxicity. Cocaine treatment significantly increased superoxide dismutase activity in as little as 1 hour, with a maximum level at 6 hours in wild-type mice, while significantly decreasing GPx activity and subsequently inducing oxidative damage (i.e., reactive oxygen species, lipid peroxidation and protein carbonylation). These changes were more prominent in the mitochondrial fraction than in the cytosolic fraction. In contrast, genetic overexpression of GPx-1 significantly attenuated cocaine-induced oxidative damage in mice. Cocaine treatment significantly increased alanine aminotransferase and aspartate aminotransferase levels in the serum. Consistently, cocaine significantly enhanced cleaved caspase-3 expression and intramitochondrial Ca2+ , while significantly reducing mitochondrial transmembrane potential. Cocaine treatment potentiated cleavage of protein kinase C δ (PKCδ), mitochondrial translocation of PKCδ, cytosolic release of cytochrome c and activation of caspase-3, followed by hepatopathologic changes. These results were more prominent in GPx-1 knockout than in wild-type mice, and they were less pronounced in overexpressing transgenic than in non-transgenic mice. Combined, our results suggest that the GPx-1 gene possesses protective potential against mitochondrial oxidative burden, mitochondrial dysfunction and hepatic degeneration induced by cocaine and that the protective mechanisms are associated with anti-apoptotic activity via inactivation of PKCδ.

Phosphatidylcholine attenuated docetaxel-induced peripheral neurotoxicity in rats.

Docetaxel is a taxane chemotherapeutic agent used in the treatment of breast cancer, prostate cancer and gastric cancer, but several side effects such as peripheral neurotoxicity could occur. The present study was designed to investigate the therapeutic potential of phosphatidylcholine (PC) on docetaxel-induced peripheral neurotoxicity. Rats were randomly divided into three groups and treated for 4 weeks. Behavioral tests were conducted to measure the effects of PC on docetaxel-induced decreases in mechanical & thermal nociceptive threshold. Biochemical tests were conducted to measure the level of oxidative stress on sciatic nerve. Histopathological and immunohistochemical experiments were also conducted to assess neuronal damage and glial activation. PC treatment significantly attenuated docetaxel-induced changes in mechanical & thermal nociceptive response latencies. PC decreased oxidative stress in sciatic nerve by increasing antioxidant levels (glutathione, glutathione peroxidase and superoxide dismutase activity). In immunohistochemical evaluation, PC treatment ameliorated docetaxel-induced neuronal damage and microglial activation in the sciatic nerve and spinal cord. Thus, PC showed protective effects against docetaxel-induced peripheral neurotoxicity. These effects may be attributed to its antioxidant properties and modulation of microglia.

YY-1224, a terpene trilactone-strengthened Ginkgo biloba, attenuates neurodegenerative changes induced by ß-amyloid (1-42) or double transgenic overexpression of APP and PS1 via inhibition of cyclooxygenase-2.

BACKGROUND: Ginkgo biloba has been reported to possess free radical-scavenging antioxidant activity and anti-inflammatory properties. In our pilot study, YY-1224, a terpene trilactone-strengthened extract of G. biloba, showed anti-inflammatory, neurotrophic, and antioxidant effects. RESULTS: We investigated the pharmacological potential of YY-1224 in ß-amyloid (Aß) (1-42)-induced memory impairment using cyclooxygenase-2 (COX-2) knockout (-/-) and APPswe/PS1dE9 transgenic (APP/PS1 Tg) mice. Repeated treatment with YY-1224 significantly attenuated Aß (1-42)-induced memory impairment in COX-2 (+/+) mice, but not in COX-2 (-/-) mice. YY-1224 significantly attenuated Aß (1-42)-induced upregulation of platelet-activating factor (PAF) receptor gene expression, reactive oxygen species, and pro-inflammatory factors. In addition, YY-1224 significantly inhibited Aß (1-42)-induced downregulation of PAF-acetylhydrolase-1 (PAF-AH-1) and peroxisome proliferator-activated receptor γ (PPARγ) gene expression. These changes were more pronounced in COX-2 (+/+) mice than in COX-2 (-/-) mice. YY-1224 significantly attenuated learning impairment, Aß deposition, and pro-inflammatory microglial activation in APP/PS1 Tg mice, whereas it significantly enhanced PAF-AH and PPARγ expression. A preferential COX-2 inhibitor, meloxicam, did not affect the pharmacological activity by YY-1224, suggesting that the COX-2 gene is a critical mediator of the neuroprotective effects of YY-1224. The protective activity of YY-1224 appeared to be more efficacious than a standard G. biloba extract (Gb) against Aß insult. CONCLUSIONS: Our results suggest that the protective effects of YY-1224 against Aß toxicity may be associated with its PAF antagonistic- and PPARγ agonistic-potential as well as inhibition of the Aß-mediated pro-inflammatory switch of microglia phenotypes through suppression of COX-2 expression.

MK-801, but not naloxone, attenuates high-dose dextromethorphan-induced convulsive behavior: Possible involvement of the GluN2B receptor.

Dextromethorphan (DM) is a dextrorotatory isomer of levorphanol, a typical morphine-like opioid. When administered at supra-antitussive doses, DM produces psychotoxic and neurotoxic effects in humans. Although DM abuse has been well-documented, few studies have examined the effects of high-dose DM. The present study aimed to explore the effects of a single high dose of DM on mortality and seizure occurrence. After intraperitoneal administration with a high dose of DM (80mg/kg), Sprague-Dawley rats showed increased seizure occurrence and intensity. Hippocampal expression levels of N-methyl-d-aspartate (NMDA) receptor subunits (GluN1

High-dose dextromethorphan produces myelinoid bodies in the hippocampus of rats.

Dextromethorphan (DM) administered at supra-antitussive doses produce psychotoxic and neurotoxic effects in humans. We administered DM (80 mg/kg) to rats intraperitoneally to determine the ultrastructural change induced by DM, because intraperitoneal route is sensitive for the behavioral responses. Treatment with DM resulted in mitochondrial dysfunction and formation of myelinoid bodies in the hippocampus. MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] attenuated DM-induced cytosolic oxidative burdens. However, neither MK-801 nor naloxone affected DM-induced mitochondrial dysfunction and formation of myelinoid bodies, indicating that the neurotoxic mechanism needs to be further elucidated. Therefore, the spectrum of toxicological effects associated with DM need to be reassessed.

Genetic overexpressing of GPx-1 attenuates cocaine-induced renal toxicity via induction of anti-apoptotic factors.

The present study investigates the role of the glutathione peroxidase (GPx)-1 gene in cocaine-induced renal damage in mice. Multiple doses of cocaine increased lipid peroxidation, protein oxidation, and glutathione oxidation in the kidney of the non-transgenic mice (non-TG mice). The enzymatic activities of GPx and glutathione reductase were significantly decreased in non-TG mice, whereas superoxide dismutase was increased in the early phase of cocaine exposure. Treatment with cocaine resulted in significant decreases in expression of Bcl-2 and Bcl-xl in the kidney of non-TG mice, which resulted in significant increases in Bax and cleaved-caspase 3. Consistently, cocaine-induced tubular epithelial vacuolization and focal tubular necrosis were mainly observed in the proximal tubules in the kidneys of non-TG mice. These renal pathologic changes were much less pronounced in GPx-1 TG than in non-TG mice. These results suggest that the GPx-1 gene is a protective factor against nephrotoxicity induced by cocaine via interactive modulations between antioxidant and cell survival signaling processes.

Effects of Aqueous Extract of Phyllostachyos Caulis in Taeniam on Longitudinal Bone Growth in Adolescent Rats.

This study examined whether treatment with Phyllostachyos Caulis in Taeniam aqueous extract improves longitudinal bone growth in adolescent male rats. Three-week-old male Sprague-Dawley rats were divided into three groups: a control group, a Phyllostachyos Caulis in Taeniam group (200 mg/kg, p.o.), and a recombinant human growth hormone group (20 µg/kg, s.c.). The total tibial length and the height of each growth plate zone were evaluated by radiography and histomorphometry. The total number of proliferative cells and 5-bromo-2'-deoxyuridine-positive cells were counted after 5-bromo-2'-deoxyuridine staining. Serum total osteocalcin levels were assayed using an enzyme-linked immunosorbent assay. The average total tibial length of the Phyllostachyos Caulis in Taeniam group was significantly longer than that of the control group. The heights of the proliferative and hypertrophic zones in the Phyllostachyos Caulis in Taeniam group were increased, and the ratio of 5-bromo-2'-deoxyuridine-positive to total cells in the proliferative zone was also increased. The serum osteocalcin, growth hormone, and insulin-like growth factor-1 levels were significantly increased in the Phyllostachyos Caulis in Taeniam group compared to the control group. Insulin-like growth factor-1 and insulin-like growth factor-1 receptor were highly expressed in the proliferative and hypertrophic zones in the Phyllostachyos Caulis in Taeniam group. The Phyllostachyos Caulis in Taeniam extract increased bone length, promoted cell proliferation, and activated the growth plate zones, which suggested that the extract could play an important role in longitudinal bone growth. Therefore, the Phyllostachyos Caulis in Taeniam extract might be a good alternative medicine to growth hormone therapy.

Clinical effect of a polysaccharide-rich extract of Acanthopanax senticosus on alcohol hangover.

The present study aimed to examine the effects polysaccharide-rich extract of Acanthopanax senticosus (PEA) on blood alcohol concentration (BAC) and hangover as well as blood lab parameters. A randomized, placebo-controlled, double-blind crossover trial was conducted. The PEA was orally administered before and after consuming alcohol 1.75 g/kg of pure alcohol. After alcohol consumption, BAC was measured for evaluation of alcohol pharmacokinetics. In the second day morning, subjects were asked to complete the Acute Hangover Scale (AHS) questionnarie. BAC results showed little difference between placebo and PEA groups, indicating that PEA does not have an effect on the pharmacokinetics of alcohol. However, several AHS items (i.e., tired, headache, dizziness, stomachache and nausea) and AHS total score were significantly improved by PEA. Blood lab parameters were significantly altered by alcohol in the placebo group. The alteration by alcohol of glucose and C-reactive protein (CRP) level was significantly attenuated by PEA. Therefore, PEA may have potential to reduce the severity of the alcohol hangover by inhibiting the alcohol-induced hypoglycemia and inflammatory response.

Extremely low frequency magnetic field modulates the level of neurotransmitters.

This study was aimed to observe that extremely low frequency magnetic field (ELF-MF) may be relevant to changes of major neurotransmitters in rat brain. After the exposure to ELF-MF (60 Hz, 2.0 mT) for 2 or 5 days, we measured the levels of biogenic amines and their metabolites, amino acid neurotransmitters and nitric oxide (NO) in the cortex, striatum, thalamus, cerebellum and hippocampus. The exposure of ELF-MF for 2 or 5 days produced significant differences in norepinephrine and vanillyl mandelic acid in the striatum, thalamus, cerebellum and hippocampus. Significant increases in the levels of serotonin and 5-hydroxyindoleacetic acid were also observed in the striatum, thalamus or hippocampus. ELF-MF significantly increased the concentration of dopamine in the thalamus. ELF-MF tended to increase the levels of amino acid neurotransmitters such as glutamine, glycine and γ -aminobutyric acid in the striatum and thalamus, whereas it decreased the levels in the cortex, cerebellum and hippocampus. ELF-MF significantly increased NO concentration in the striatum, thalamus and hippocampus. The present study has demonstrated that exposure to ELF-MFs may evoke the changes in the levels of biogenic amines, amino acid and NO in the brain although the extent and property vary with the brain areas. However, the mechanisms remain further to be characterized.

Melatonin attenuates memory impairment induced by Klotho gene deficiency via interactive signaling between MT2 receptor, ERK, and Nrf2-related antioxidant potential.

BACKGROUND: We demonstrated that oxidative stress plays a crucial role in cognitive impairment in klotho mutant mice, a genetic model of aging. Since down-regulation of melatonin due to aging is well documented, we used this genetic model to determine whether the antioxidant property of melatonin affects memory impairment. METHODS: First, we examined the effects of melatonin on hippocampal oxidative parameters and the glutathione/oxidized glutathione (GSH/GSSG) ratio and memory dysfunction of klotho mutant mice. Second, we investigated whether a specific melatonin receptor is involved in the melatonin-mediated pharmacological response by application with melatonin receptor antagonists. Third, we examined phospho-extracellular-signal-regulated kinase (ERK) expression, nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, Nrf2 DNA binding activity, and glutamate-cysteine ligase (GCL) mRNA expression. Finally, we examined effects of the ERK inhibitor SL327 in response to antioxidant efficacy and memory enhancement mediated by melatonin. RESULTS: Treatment with melatonin resulted in significant attenuations of oxidative damage, a decrease in the GSH/GSSG ratio, and a significant amelioration of memory impairment in this aging model. These effects of melatonin were significantly counteracted by the selective MT2 receptor antagonist 4-P-PDOT. Importantly, 4-P-PDOT or SL327 also counteracted melatonin-mediated attenuation in response to the decreases in phospho-ERK expression, Nrf2 nuclear translocation, Nrf2 DNA-binding activity, and GCL mRNA expression in the hippocampi of klotho mutant mice. SL327 also counteracted the up-regulation of the GSH/GSSG ratio and the memory enhancement mediated by melatonin in klotho mutant mice. CONCLUSIONS: Melatonin attenuates oxidative stress and the associated memory impairment induced by klotho deficiency via signaling interaction between the MT2 receptor and ERK- and Nrf2-related antioxidant potential.

Anti-gastritis and wound healing effects of Momordicae Semen extract and its active component.

Momordicae Semen, Momordica cochinchinensis Springer (Cucurbitaceae), has long been known to effectively relieve boils, rheumatic pain, and hemorrhoids. In this study, we investigated whether Momordicae Semen extract (MSE) has anti-gastritis effects in various rodent models and also explored possible mechanisms for the gastroprotective effects of MSE. MSE provided remarkable protective effects, comparable to those of rebamipide, in ethanol- and diclofenac-induced acute gastritis. In addition, it has demonstrated protective effect in a Helicobacter pylori-insulted chronic gastritis model. MSE also showed wound healing effect on cutaneous injury of mice and stimulated calcitonin gene-related peptide and somatostatin receptors, which may be related to its anti-gastritis effects. In a single oral dose toxicity study, the approximate lethal dose of MSE was determined at >2000 mg/kg/day. The NOAEL was set to be 2000 mg/kg/day from the repeated oral dose toxicity study. Moreover, momordica saponin I, a major ingredient of MSE, treatment decreased gastric mucosa damage indices in the ethanol- and diclofenac-induced acute gastritis models. The results suggest that MSE could be a promising gastroprotective herbal medicine and momordica saponin I might be used as an active marker compound for MSE.