Lipid signatures reflect the function of the murine primary placentation†.

The placenta regulates maternal-fetal communication, and its defect leads to significant pregnancy complications. The maternal and embryonic circulations are primitively connected in early placentation, but the function of the placenta during this developmentally essential period is relatively unknown. We thus performed a comparative proteomic analysis of the placenta before and after primary placentation and found that the metabolism and transport of lipids were characteristically activated in this period. The placental fatty acid (FA) carriers in specific placental compartments were upregulated according to gestational age, and metabolomic analysis also showed that the placental transport of FAs increased in a time-dependent manner. Further analysis of two mutant mice models with embryonic lethality revealed that lipid-related signatures could reflect the functional state of the placenta. Our findings highlight the importance of the nutrient transport function of the primary placenta in the early gestational period and the role of lipids in embryonic development. SUMMARY SENTENCE: The placenta is activated characteristically in terms of lipid transport during primary placentation, and the lipid-related signatures closely reflect the functional state of the placenta.

Progesterone receptor membrane component 1 is required for mammary gland development†.

The physiological functions of progesterone (P4) in female reproductive organs including the mammary glands are mediated via the progesterone receptor (PR), but not all P4 functions can be explained by PR-mediated signaling. Progesterone receptor membrane component 1 (PGRMC1), a potential mediator of P4 actions, plays an important role in the ovary and uterus in maintaining female fertility and pregnancy, but its function in mammary glands has not been elucidated. This study investigated the role of PGRMC1 in mouse mammary gland development. Unlike in the uterus, exogenous estrogen (E2) and/or P4 did not alter PGRMC1 expression in the mammary gland, and Pgrmc1-knockout (KO) mice displayed reduced ductal elongation and side branching in response to hormone treatment. During pregnancy, PGRMC1 was expressed within both the luminal and basal epithelium and gradually increased with gestation and decreased rapidly after parturition. Moreover, although lactogenic capacity was normal after parturition, Pgrmc1 KO resulted in defective mammary gland development from puberty until midpregnancy, while the expression of PR and its target genes was not significantly different between wild-type and Pgrmc1-KO mammary gland. These data suggest that PGRMC1 is essential for mammary gland development during puberty and pregnancy in a PR-independent manner.

Cereboost™, an American ginseng extract, improves cognitive function via up-regulation of choline acetyltransferase expression and neuroprotection.

In Alzheimer disease (AD), amyloid-beta (Aß) peptides induce the degeneration of presynaptic cholinergic system, in which decreased activity of enzyme choline acetyltransferase (ChAT) responsible for acetylcholine synthesis is observed. Cereboost™, an extract of American ginseng extract, contains a high concentration of Rb1 ginsenoside which is a well-known ingredient improving human cognitive function. We investigated the effects of Cereboost™ on learning and memory function of mice challenged with an Aß1-42 peptide and the underlying mechanisms in vitro. Cereboost™ protected against Aß1-42-induced cytotoxicity in F3.ChAT stem cells, and enhanced the ChAT gene expression. Aß1-42 injection into the mouse brain impaired the cognitive function, which was recovered by oral administration of Cereboost™. In addition, Cereboost™ restored brain microtubule-associated protein 2 and synaptophysin as well as acetylcholine concentration. The results demonstrate that Cereboost™ administration recovered the cognitive function of AD model animals by enhancing acetylcholine level via ChAT gene expression and neuroprotection.

4-O-methylhonokiol inhibits serious embryo anomalies caused by nicotine via modulations of oxidative stress, apoptosis, and inflammation.

BACKGROUND: Since the increasing smoking rate among women has resulted in higher rates of embryonic malformations, it is important to search for an efficient and inexpensive agent that can help reduce the rate of serious fetal anomalies caused by maternal cigarette smoking. In this study, the bioavailability of 4-O-methylhonokiol isolated from Magnolia officinalis was first demonstrated in the mouse embryos exposed to nicotine using a whole embryo culture system. METHODS: Mouse embryos on embryonic day 8.5 were cultured with 1 mM nicotine and/or 4-O-methylhonokiol (1 × 10(-4) or 1 × 10(-3) µM) for 48 hr and were analyzed on the viewpoints of embryo developmental changes, oxidative damages, and apoptotic and inflammatory changes. RESULTS: Embryos exposed to 1 mM nicotine developed not only severe morphological anomalies, increased expressions of tumor necrosis factor-α, interleukin-1ß, and caspase 3 mRNAs; and elevated levels of lipid peroxidation, but also decreased levels of cytoplasmic superoxide dismutase, cytosolic glutathione peroxidase, phospholipid hydroperoxide glutathione peroxidase, hypoxia inducible factor-1α, and B-cell lymphoma-extra large mRNAs, and reduced superoxide dismutase activity. However, these parameters were significantly improved when embryos exposed to the nicotine were concurrently treated with 4-O-methylhonokiol (1 × 10(-4) or 1 × 10(-3) µM). CONCLUSIONS: These findings indicate that 4-O-methylhonokiol reduces serious embryo anomalies caused by nicotine in mouse embryos via the modulations of oxidative stress, apoptosis, and inflammation, suggesting that 4-O-methylhonokiol may be a preventive and therapeutic agent against the dysmorphology induced by maternal smoking during pregnancy.

PIBF1 regulates trophoblast syncytialization and promotes cardiovascular development.

Proper placental development in early pregnancy ensures a positive outcome later on. The developmental relationship between the placenta and embryonic organs, such as the heart, is crucial for a normal pregnancy. However, the mechanism through which the placenta influences the development of embryonic organs remains unclear. Trophoblasts fuse to form multinucleated syncytiotrophoblasts (SynT), which primarily make up the placental materno-fetal interface. We discovered that endogenous progesterone immunomodulatory binding factor 1 (PIBF1) is vital for trophoblast differentiation and fusion into SynT in humans and mice. PIBF1 facilitates communication between SynT and adjacent vascular cells, promoting vascular network development in the primary placenta. This process affected the early development of the embryonic cardiovascular system in mice. Moreover, in vitro experiments showed that PIBF1 promotes the development of cardiovascular characteristics in heart organoids. Our findings show how SynTs organize the barrier and imply their possible roles in supporting embryogenesis, including cardiovascular development. SynT-derived factors and SynT within the placenta may play critical roles in ensuring proper organogenesis of other organs in the embryo.

Emodin prevents ethanol-induced developmental anomalies in cultured mouse fetus through multiple activities.

BACKGROUND: Maternal alcohol ingestion on pregnant period causes fetal alcohol syndrome including psychological and behavioral problems, and developmental abnormality. In this study, we investigated the effect of emodin, an active anthraquinone component found in the roots and bark of the genus Rhamnus (Buckthorn), on ethanol-induced teratogenesis during embryonic organogenesis. METHODS: We cultured mouse embryos on embryonic day 8.5 for 2 days with ethanol (5 µl/3 ml) and/or emodin (1×10(-5) and 1×10(-4) µg/ml) using a whole embryo culture system and then investigated the developmental evaluation, superoxide dismutase (SOD) activity, and expression patterns of cytoplasmic SOD (SOD1), mitochondrial SOD (SOD2), cytosolic glutathione peroxidase (cGPx), tumor necrosis factor-α (TNF-α), caspase 3, and hypoxia inducible factor 1α (HIF-1α). RESULTS: Morphological parameters, including growth in yolk sac and fetal head, body length, and development of the central nervous system, circulation system, sensory organs, skeletal system, and limbs in embryos exposed to ethanol were significantly decreased compared to those of the normal control group, but co-treatment with emodin (1 × 10(-5) and 1 × 10(-4) µg/ml) significantly improved these parameters. Furthermore, the reduced levels of SOD activity, and SOD1, SOD2, cGPx, and HIF-1α and the increased gene levels of TNF-α and caspase-3 due to ethanol exposure were significantly restored by cotreatment with emodin. Birth Defects Res (Part B) 98:268-275, 2013. © 2013 Wiley Periodicals, Inc. CONCLUSIONS: This study revealed that cotreatment with emodin significantly prevented teratogenesis induced by ethanol, not only by modulating hypoxia and antioxidant enzymes, but also by attenuating the enhanced levels of TNF-α and caspase 3 in cultured embryos. Therefore, emodin may be an effective preventive agent for ethanol-induced teratogenesis.

Predicting multipotency of human adult stem cells derived from various donors through deep learning.

Adult stem cell-based therapeutic approaches have great potential in regenerative medicine because of their immunoregulatory properties and multidifferentiation capacity. Nevertheless, the outcomes of stem cell­based therapies to date have shown inconsistent efficacy owing to donor variation, thwarting the expectation of clinical effects. However, such donor dependency has been elucidated by biological consequences that current research could not predict. Here, we introduce cellular morphology-based prediction to determine the multipotency rate of human nasal turbinate stem cells (hNTSCs), aiming to predict the differentiation rate of keratocyte progenitors. We characterized the overall genes and morphologies of hNTSCs from five donors and compared stemness-related properties, including multipotency and specific lineages, using mRNA sequencing. It was demonstrated that transformation factors affecting the principal components were highly related to cell morphology. We then performed a convolutional neural network-based analysis, which enabled us to assess the multipotency level of each cell group based on their morphologies with 85.98% accuracy. Surprisingly, the trend in expression levels after ex vivo differentiation matched well with the deep learning prediction. These results suggest that AI­assisted cellular behavioral prediction can be utilized to perform quantitative, non-invasive, single-cell, and multimarker characterizations of live stem cells for improved quality control in clinical cell therapies.

Protective Effect of Human-Neural-Crest-Derived Nasal Turbinate Stem Cells against Amyloid-ß Neurotoxicity through Inhibition of Osteopontin in a Human Cerebral Organoid Model of Alzheimer's Disease.

The aim of this study was to validate the use of human brain organoids (hBOs) to investigate the therapeutic potential and mechanism of human-neural-crest-derived nasal turbinate stem cells (hNTSCs) in models of Alzheimer's disease (AD). We generated hBOs from human induced pluripotent stem cells, investigated their characteristics according to neuronal markers and electrophysiological features, and then evaluated the protective effect of hNTSCs against amyloid-ß peptide (Aß1-42) neurotoxic activity in vitro in hBOs and in vivo in a mouse model of AD. Treatment of hBOs with Aß1-42 induced neuronal cell death concomitant with decreased expression of neuronal markers, which was suppressed by hNTSCs cocultured under Aß1-42 exposure. Cytokine array showed a significantly decreased level of osteopontin (OPN) in hBOs with hNTSC coculture compared with hBOs only in the presence of Aß1-42. Silencing OPN via siRNA suppressed Aß-induced neuronal cell death in cell culture. Notably, compared with PBS, hNTSC transplantation significantly enhanced performance on the Morris water maze, with reduced levels of OPN after transplantation in a mouse model of AD. These findings reveal that hBO models are useful to evaluate the therapeutic effect and mechanism of stem cells for application in treating AD.

Potential application of human neural crest-derived nasal turbinate stem cells for the treatment of neuropathology and impaired cognition in models of Alzheimer's disease.

BACKGROUND: Stem cell transplantation is a fascinating therapeutic approach for the treatment of many neurodegenerative disorders; however, clinical trials using stem cells have not been as effective as expected based on preclinical studies. The aim of this study is to validate the hypothesis that human neural crest-derived nasal turbinate stem cells (hNTSCs) are a clinically promising therapeutic source of adult stem cells for the treatment of Alzheimer's disease (AD). METHODS: hNTSCs were evaluated in comparison with human bone marrow-derived mesenchymal stem cells (hBM-MSCs) according to the effect of transplantation on AD pathology, including PET/CT neuroimaging, immune status indicated by microglial numbers and autophagic capacity, neuronal survival, and cognition, in a 5 × FAD transgenic mouse model of AD. RESULTS: We demonstrated that hNTSCs showed a high proliferative capacity and great neurogenic properties in vitro. Compared with hBM-MSC transplantation, hNTSC transplantation markedly reduced Aß42 levels and plaque formation in the brains of the 5 × FAD transgenic AD mice on neuroimaging, concomitant with increased survival of hippocampal and cortex neurons. Moreover, hNTSCs strongly modulated immune status by reducing the number of microglia and the expression of the inflammatory cytokine IL-6 and upregulating autophagic capacity at 7 weeks after transplantation in AD models. Notably, compared with transplantation of hBM-MSCs, transplantation of hNTSCs significantly enhanced performance on the Morris water maze, with an increased level of TIMP2, which is necessary for spatial memory in young mice and neurons; this difference could be explained by the high engraftment of hNTSCs after transplantation. CONCLUSION: The reliable evidence provided by these findings reveals a promising therapeutic effect of hNTSCs and indicates a step forward the clinical application of hNTSCs in patients with AD.

Loss of PGRMC1 Delays the Progression of Hepatocellular Carcinoma via Suppression of Pro-Inflammatory Immune Responses.

Pgrmc1 is a non-canonical progesterone receptor related to the lethality of various types of cancer. PGRMC1 has been reported to exist in co-precipitated protein complexes with epidermal growth factor receptor (EGFR), which is considered a useful therapeutic target in hepatocellular carcinoma (HCC). Here, we investigated whether Pgrmc1 is involved in HCC progression. In clinical datasets, PGRMC1 transcription level was positively correlated with EGFR levels; importantly, PGRMC1 level was inversely correlated with the survival duration of HCC patients. In a diethylnitrosamine (DEN)-induced murine model of HCC, the global ablation of Pgrmc1 suppressed the development of HCC and prolonged the survival of HCC-bearing mice. We further found that increases in hepatocyte death and suppression of compensatory proliferation in the livers of DEN-injured Pgrmc1-null mice were concomitant with decreases in nuclear factor κB (NF-κB)-dependent production of interleukin-6 (IL-6). Indeed, silencing of Pgrmc1 in murine macrophages led to reductions in NF-κB activity and IL-6 production. We found that the anti-proinflammatory effect of Pgrmc1 loss was mediated by reductions in EGFR level and its effect was not observed after exposure of the EGFR inhibitor erlotinib. This study reveals a novel cooperative role of Pgrmc1 in supporting the EGFR-mediated development of hepatocellular carcinoma, implying that pharmacological suppression of Pgrmc1 may be a useful strategy in HCC treatment.

Korean red ginseng extract does not cause embryo-fetal death or abnormalities in mice.

BACKGROUND: Ginseng has been used for a long time and is well tolerated in humans. However, recent studies have shown that ginsenosides Rb1, Rg1, and Re exert embryotoxicity in in vitro culture systems. We investigated the effects of Korean red ginseng extract (KRGE) on embryonic implantation and fetal development in mice. METHODS: Mice were orally administered KRGE (20, 200, or 2,000 mg/kg/day) from 2 weeks before mating to gestational day (GD) 18, and implantation rate, fetal mortality, body weights, as well as external, visceral, and skeletal abnormalities were determined by Caesarean section on GD18. Ginsenosides in KRGE and in the blood of dams were identified and quantified by HPLC analysis. RESULTS: KRGE did not affect embryonic implantation and mortality as well as fetal body weights up to 2,000 mg/kg/day (approximately 200 times clinical doses), the upper-limit dose recommended by the Korea Food and Drug Administration (KFDA). Although the prevalence of supernumerary ribs increased at the medium dose (200 mg/kg/day), no dose-dependent increases in external, visceral, and skeletal abnormalities were observed. Major ginsenosides such as Rb1, Rg1, and Re were not detected in the blood of dams based on their chromatographic profiles. CONCLUSIONS: Considerable developmental toxicities of KRGE, even at the upper-limit dose, were not observed in mice. These results might be due to the negligible blood concentrations of ginsenosides in their original forms following oral administration, suggesting that in vitro experiments to assess the effects of ginsenosides on embryotoxicity may not reliably explain the risks of ginsenosides to in vivo embryo-fetal development.

Black ginseng inhibits ethanol-induced teratogenesis in cultured mouse embryos through its effects on antioxidant activity.

Fetal alcohol syndrome is caused by excessive ethanol consumption during pregnancy. We investigated the effect of black ginseng (red ginseng that is subjected to 9 cycles of 95-100 degrees C for 2-3h) on ethanol-induced teratogenesis using an in vitro whole embryo culture system. Postimplantational mouse embryos at embryonic day 8.5 were exposed to ethanol (1 microl/ml) in the presence or absence of black ginseng (1, 10, and 100 microg/ml) for 2 days, and then morphological scoring and real-time PCR analysis were carried out. In ethanol-treated embryos, the total morphological score and individual scores for flexion, heart, fore-, mid-, and hindbrains, otic, optic, and olfactory systems, branchial bars, maxillary and mandibular processes, caudal neural tube, and somites were significantly lower than the control group (p<0.05). Treatment with black ginseng improved most of the morphological scores significantly as compared to ethanol-treated embryos (p<0.05). The mRNA levels of the antioxidant enzymes cytosolic glutathione peroxidase (GPx), phospholipid hydroperoxide GPx, and selenoprotein P were significantly decreased in ethanol-treated embryos, but co-treatment with black ginseng restored the mRNA levels to those of control embryos. These results indicate that black ginseng has a protective effect on ethanol-induced teratogenesis through the augmentation of antioxidative activity in embryos.

Spatiotemporal expression of the selenoprotein P gene in postimplantational mouse embryos.

Selenoprotein P (Sepp) is an extracellular glycoprotein which functions principally as a selenium (Se) transporter and antioxidant. In order to assess the spatiotemporal expression of the Sepp gene during mouse embryogenesis, quantitative RT-PCR and in situ hybridization analyses were conducted in embryos and extraembryonic tissues, including placenta. Sepp mRNA expression was detected in all embryos and extraembryonic tissues on embryonic days (E) 7.5 to 18.5. Sepp mRNA levels were high in extraembryonic tissues, as compared to embryos, on E 7.5-13.5. However, the levels were higher in embryos than in extraembryonic tissues on E 14.5-15.5, but were similar in both tissues during the subsequent periods prior to birth. According to the results of in situ hybridization, Sepp mRNA was expressed principally in the ectoplacental cone and neural ectoderm, including the neural tubes and neural folds. In whole embryos, Sepp mRNA was expressed abundantly in nervous tissues on E 9.5-12.5. Sepp mRNA was also expressed in forelimb and hindlimb buds on E 10.5-12.5. In the sectioned embryos, on E 13.5-18.5, Sepp mRNA was expressed persistently in the developing limbs, gastrointestinal tract, nervous tissue, lung, kidney and liver. On E 16.5-18.5, Sepp mRNA expression in the submandibular gland, whisker follicles, pancreas, urinary bladder and skin was apparent. In particular, Sepp mRNA was detected abundantly in blood cells during all the observed developmental periods. These results show that Sepp may function as a transporter of selenium, as well as an antioxidant, during embryogenesis.

The spatio-temporal expression pattern of cytoplasmic Cu/Zn superoxide dismutase (SOD1) mRNA during mouse embryogenesis.

The cytoplasmic Cu/Zn-superoxide dismutase (SOD1) represents along with catalase and glutathione peroxidase at the first defense line against reactive oxygen species in all aerobic organisms, but little is known about its distribution in developing embryos. In this study, the expression patterns of SOD1 mRNA in mouse embryos were investigated using real-time RT-PCR and in situ hybridization analyses. Expression of SOD1 mRNA was detected in all embryos with embryonic days (EDs) 7.5-18.5. The signal showed the weakest level at ED 12.5, but the highest level at ED 15.5. SOD1 mRNA was expressed in chorion, allantois, amnion, and neural folds at ED 7.5 and in neural folds, notochord, neuromeres, gut, and primitive streak at ED 8.5. In central nervous system, SOD1 mRNA was expressed greatly in embryos of EDs 9.5-11.5, but weakly in embryos of ED 12.5. At EDs 9.5-12.5, the expression of SOD1 mRNA was high in sensory organs such as tongue, olfactory organ (nasal prominence) and eye (optic vesicle), while it was decreased in ear (otic vesicle) after ED 10.5. In developing limbs, SOD1 mRNA was greatly expressed in forelimbs at EDs 9.5-11.5 and in hindlimbs at EDs 10.5-11.5. The signal increased in liver, heart and genital tubercle after ED 11.5. In the sections of embryos after ED 13.5, SOD1 mRNA was expressed in various tissues and especially high in mucosa and metabolically active sites such as lung, kidney, stomach, and intestines and epithelial cells of skin, whisker follicles, and ear and nasal cavities. These results suggest that SOD1 may be related to organogenesis of embryos as an antioxidant enzyme.

Capsaicin prevents ethanol-induced teratogenicity in cultured mouse whole embryos.

Prenatal exposure to alcohol promotes the level of reactive oxygen species within embryos and results in developmental disorders. In this study, we investigated the effect of capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), the major pungent ingredient in red peppers, on ethanol-induced teratogenicity in mouse embryos (embryonic days 8.5-10.5). In response to ethanol administration (1.0 microl/ml), developmental parameters such as yolk sac circulation, allantois, heart, hindbrain, midbrain, forebrain, otic and optic systems, branchial bar, olfactory system, forelimb, hindlimb, and somites decreased significantly in comparison with those of control group (p<0.05). However, the concurrent administration of capsaicin (1 x 10(-8) microg/ml or 1 x 10(-7) microg/ml) and ethanol significantly ameliorated most of the morphological scores excepting yolk sac circulation and hindlimb scores (p<0.05). Furthermore, the levels of superoxide dismutase activity and cytoplasmic glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase mRNAs in the ethanol-treated embryos recovered to the levels observed in control embryos by capsaicin co-administration. These results indicate that capsaicin has a protective effect against ethanol-induced teratogenicity via an antioxidative activity.

Licorice extract does not impair the male reproductive function of rats.

The effect of water extract of licorice (Glycyrrhiza uralensis), one of the most widely used medicinal plants in Oriental nations and in Europe, on male reproductive function was investigated in rats. Licorice extract was prepared as in Oriental clinics and orally administered at doses of 500, 1,000 or 2,000 mg/kg, the upper-limit dose (2,000 mg/kg) recommended in the Toxicity Test guideline of the Korea Food and Drug Administration, to 6-week-old male rats for 9 weeks. Licorice extract neither induced clinical signs, nor affected the daily feed consumption and body weight gain. There were no significant changes in testicular weights, gross and microscopic findings, and daily sperm production between vehicle- and licorice-treated animals, in spite of slight decreases in prostate weight and daily sperm production at the high dose (2,000 mg/kg). In addition, licorice did not affect the motility and morphology of sperm, although the serum testosterone level tended to decrease without significant difference, showing a 28.6% reduction in the high-dose (2,000 mg/kg) group. The results suggest that the no observed adverse-effect level of licorice extract is higher than 2,000 mg/kg, the upper-limit dose, and that long-term exposure to licorice might not cause profound adverse effects.

Immunohistochemical identification and quantitative analysis of cytoplasmic Cu/Zn superoxide dismutase in mouse organogenesis.

Cytoplasmic Cu/Zn superoxide dismutase (SOD1) is an antioxidant enzyme that converts superoxide to hydrogen peroxide in cells. Its spatial distribution matches that of superoxide production, allowing it to protect cells from oxidative stress. SOD1 deficiencies result in embryonic lethality and a wide range of pathologies in mice, but little is known about normal SOD1 protein expression in developing embryos. In this study, the expression pattern of SOD1 was investigated in post-implantation mouse embryos and extraembryonic tissues, including placenta, using Western blotting and immunohistochemical analyses. SOD1 was detected in embryos and extraembryonic tissues from embryonic day (ED) 8.5 to 18.5. The signal in embryos was observed at the lowest level on ED 9.5-11.5, and the highest level on ED 17.5-18.5, while levels remained constant in the surrounding extraembryonic tissues during all developmental stages examined. Immunohistochemical analysis of SOD1 expression on ED 13.5-18.5 revealed its ubiquitous distribution throughout developing organs. In particular, high levels of SOD1 expression were observed in the ependymal epithelium of the choroid plexus, ganglia, sensory cells of the olfactory and vestibulocochlear epithelia, blood cells and vessels, hepatocytes and hematopoietic cells of the liver, lymph nodes, osteogenic tissues, and skin. Thus, SOD1 is highly expressed at late stages of embryonic development in a cell- and tissue-specific manner, and can function as an important antioxidant enzyme during organogenesis in mouse embryos.

The Ethanol Fraction of White Rose Petal Extract Abrogates Excitotoxicity-Induced Neuronal Damage In Vivo and In Vitro through Inhibition of Oxidative Stress and Proinflammation.

Since oxidative stress and inflammation are involved in seizure-related neurotoxicity, the neuroprotective effect of a white rose (Rosa hybrida) petal extract (WRPE) in mice that are challenged with kainic acid (KA) were examined using behavioral epileptiform seizures as well as biochemical and morphological parameters of oxidative stress and inflammation. WRPE (50⁻200 mg/kg) was orally administered to male ICR mice for 15 days, and intraperitoneally challenged with KA (30 mg/kg). Seizure activity, lipid peroxidation, inflammatory cytokines, and related enzymes were analyzed in the brain tissue, in addition to the morphological alterations in the hippocampal pyramidal neurons. Separately, antioxidant ingredients in WRPE were analyzed, and antioxidant, anti-inflammatory, and neuroprotective activities of WRPE were investigated in HB1.F3 human neural stem cells (NSCs) to elucidate underlying mechanisms. Total polyphenol and flavonoid contents in WRPE were 303.3 ± 15.3 mg gallic acid equivalent/g extract and 18.5 ± 2.2 mg catechin/g extract, respectively. WRPE exhibited strong radical-scavenging activities and inhibited lipid peroxidation in vitro, and protected glutamate-induced cytotoxicity in NSCs by suppressing inflammatory process. Treatment with WRPE attenuated epileptiform seizure scores to a half level in KA-challenged mice, and decreased hippocampal pyramidal neuronal injury and loss (cresyl violet and DAPI staining) as well as astrocyte activation (GFAP immunostaining). Lipid peroxidation was inhibited, and mRNA expression of antioxidant enzymes (GPx, PHGPx, SOD1, and SOD2) were recovered in the brain tissues. Inflammatory parameters (cytokines and enzymes) including NF-kB, IL-1ß, TNF-α, IL-6, HMGB1, TGF-ß, iNOS, COX2, and GFAP mRNAs and proteins were also down-regulated by WRPE treatment. Taken together, the results indicate that WRPE could attenuate KA-induced brain injury through antioxidative and anti-inflammatory activities.

Corrigendum to "A Hop Extract Lifenol® Improves Postmenopausal Overweight, Osteoporosis, and Hot Flash in Ovariectomized Rats".

[This corrects the article DOI: 10.1155/2018/2929107.].

A Hop Extract Lifenol® Improves Postmenopausal Overweight, Osteoporosis, and Hot Flash in Ovariectomized Rats.

Objective: In order to assess the effectiveness of a hop extract (HE) for postmenopausal symptoms, the effects of Lifenol on ovariectomy-induced osteoporosis, hyperlipidemia, body weight increase, and hot flash were investigated in rats. Methods: Female Sprague-Dawley rats were ovariectomized and subjected to a daily scheduled exercise training (15 min at 15 m/min) or treated with HE (30 or 100 mg/kg, oral) or 17ß-estradiol (100 µg/kg, intraperitoneal) for 12 weeks. Body and visceral fat weights, serum lipid profiles, osteoporotic parameters in serum, and femoral bones were analyzed. Separately, forced running-induced dermal and rectal temperatures and blood flow velocity were measured in ovariectomized rats. Results: Ovariectomy increased blood lipids including triglycerides, total cholesterol, and low-density lipoproteins, leading to visceral fat accumulation and overweight. Estrogen depletion caused osteoporosis, displaying decreased femoral bone weight, bone mineral density and content, and blood phosphorus level. The disturbances in lipid metabolism and bone resorption were recovered by treatment with HE in a dose-dependent manner. In addition, HE treatment shortened the duration of forced running-induced alterations in skin and rectal temperatures by reducing blood flow velocity. Conclusion: The results indicate that HE attenuated overweight, osteoporosis, and hot flash in estrogen-deficient animals by regulating blood lipid profile and fat accumulation, blood estrogen and bone resorption factors, and dermal blood flow.