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Background Gintonin is a ginseng-derived exogenous G-protein-coupled lysophosphatidic acid (LPA) receptor ligand. Gintonin exerts its neuronal and non-neuronal in vitro and in vivo effects through LPA receptor subtypes. However, it is unknown whether gintonin can bind to the plasma membrane of cells and can transactivate the epidermal growth factor (EGF) receptor. In the present study, we examined whether gintonin-biotin conjugates directly bound to LPA receptors and transactivated the EGF receptor. Methods We designed gintonin-biotin conjugates through gintonin biotinylation and examined whether gintonin-biotin conjugate binding sites co-localized with the LPA receptor subtype binding sites. We further examined whether gintonin-biotin transactivated the EGF receptor via LPA receptor regulation via phosphor-EGF and cell migration assays. Results Gintonin-biotin conjugates elicit [Ca2+]i transient similar to that observed with unbiotinylated gintonin in cultured PC3 cells, suggesting that biotinylation does not affect physiological activity of gintonin. We proved that gintonin-biotin conjugate binding sites co-localized with the LPA1/6 receptor binding sites. Gintonin-biotin binding to the LPA1 receptor transactivates the epidermal growth factor (EGF) receptor through phosphorylation, while the LPA1/3 receptor antagonist, Ki16425, blocked phosphorylation of the EGF receptor. Additionally, an EGF receptor inhibitor AG1478 blocked gintonin-biotin conjugate-mediated cell migration. Conclusions We observed the binding between ginseng-derived gintonin and the plasma membrane target proteins corresponding to the LPA1/6 receptor subtypes. Moreover, gintonin transactivated EGF receptors via LPA receptor regulation. Our results suggest that gintonin directly binds to the LPA receptor subtypes and transactivates the EGF receptor. It may explain the molecular basis of ginseng physiology/pharmacology in biological systems.

Background Gintonin is an exogenous ginseng-derived G-protein-coupled lysophosphatidic acid (LPA) receptor ligand. LPA induces in vitro morphological changes and migration through neuronal LPA1 receptor. Recently, we reported that systemic administration of gintonin increases blood-brain barrier (BBB) permeability via the paracellular pathway and its binding to brain neurons. However, little is known about the influences of gintonin on in vivo neuron morphology and migration in the brain. Materials and methods We examined the effects of gintonin on in vitro migration and morphology using primary hippocampal neural precursor cells (hNPC) and in vivo effects of gintonin on adult brain neurons using real time microscopic analysis and immunohistochemical analysis to observe the morphological and locational changes induced by gintonin treatment. Results We found that treating hNPCs with gintonin induced morphological changes with a cell rounding following cell aggregation and return to individual neurons with time relapses. However, the in vitro effects of gintonin on hNPCs were blocked by the LPA1/3 receptor antagonist, Ki16425, and Rho kinase inhibitor, Y27632. We also examined the in vivo effects of gintonin on the morphological changes and migration of neurons in adult mouse brains using anti-NeuN and -neurofilament H antibodies. We found that acute intravenous administration of gintonin induced morphological and migrational changes in brain neurons. Gintonin induced some migrations of neurons with shortened neurofilament H in the cortex. The in vivo effects of gintonin were also blocked by Ki16425. Conclusion The present report raises the possibility that gintonin could enter the brain and exert its influences on the migration and morphology of adult mouse brain neurons and possibly explains the therapeutic effects of neurological diseases behind the gintonin administration.

Background Multiple sclerosis (MS) and its animal model, the experimental autoimmune encephalomyelitis (EAE), are primarily characterized as dysfunction of the blood-brain barrier (BBB). Ginsenoside-Rg3-enriched Korean red ginseng extract (Rg3-KRGE) is known to exert neuroprotective, anti-inflammatory, and anti-oxidative effects on neurological disorders. However, effects of Rg3-KRGE in EAE remain unclear. Methods Here, we investigated whether Rg3-KRGE may improve the symptoms and pathological features of myelin oligodendroglial glycoprotein (MOG)35-55 peptide – induced chronic EAE mice through improving the integrity of the BBB. Results Rg3-KRGE decreased EAE score and spinal demyelination. Rg3-KRGE inhibited Evan's blue dye leakage in spinal cord, suppressed increases of adhesion molecule platelet endothelial cell adhesion molecule-1, extracellular matrix proteins fibronection, and matrix metallopeptidase-9, and prevented decreases of tight junction proteins zonula occludens-1, claudin-3, and claudin-5 in spinal cord following EAE induction. Rg3-KRGE repressed increases of proinflammatory transcripts cyclooxygenase-2, inducible nitric oxide synthase, interleukin (IL)-1 beta, IL-6, and tumor necrosis factor-alpha, but enhanced expression levels of anti-inflammatory transcripts arginase-1 and IL-10 in the spinal cord following EAE induction. Rg3-KRGE inhibited the expression of oxidative stress markers (MitoSOX and 4-hydroxynonenal), the enhancement of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and NOX4, and NADPH activity in the spinal cord of chronic EAE mice. Furthermore, apocynin, a NOX inhibitor, mimicked beneficial effects of Rg3-KRGE in chronic EAE mice. Conclusion Our findings suggest that Rg3-KRGE might alleviate behavioral symptoms and pathological features of MS by improving BBB integrity through modulation of NOX2/4 expression.

Background Ginseng has been widely used as a health-promoting tonic. Gintonin present in ginseng acts as a lysophosphatidic acid (LPA) receptor ligand that activates six LPA receptor subtypes. The LPA6 subtype plays a key role in normal hair growth, and mutations in the LPA6 receptor impair normal human hair growth. Currently, human hair loss and alopecia are concerning issues that affect peoples' social and day-to-day lives. Objective We investigated the in vitro and in vivo effects of a gintonin-enriched fraction (GEF) on mouse hair growth. Methods Human hair follicle dermal papilla cells (HFDPCs) and six-week-old male C57BL/6 mice were used. The mice were divided into the four groups: control, 1% minoxidil, 0.75% GEF, and 1.5% GEF. The dorsal hair was removed to synchronize the telogen phase. Each group was treated topically, once a day, for 15 days. We analyzed hair growth activity and histological changes. Results GEF induced transient [Ca2+]i, which stimulated HFDPC proliferation and caused 5-bromo-2′-deoxyuridine (BrdU) incorporation in a concentration-dependent manner. GEF-mediated HFDPC proliferation was blocked by the LPA receptor antagonist and Ca2+ chelator. HFDPC treatment with GEF stimulated vascular endothelial growth factor release. Topical application of GEF and minoxidil promoted hair growth in a dose-dependent manner. Histological analysis showed that GEF and minoxidil increased the number of hair follicles and hair weight. Conclusion Topical application of GEF promotes mouse hair growth through HFDPC proliferation. GEF could be one of the main components of ginseng that promote hair growth and could be used to treat human alopecia., Highlights • Gintonin is a novel ginseng-derived lysophosphatidic acid (LPA) receptor ligand. • LPA receptor is involved in human hair growth. • Gintonin-enriched fraction (GEF) stimulates proliferation of human hair follicle dermal papilla cells via the LPA receptor. • Topical application of GEF promotes mouse hair growth. • GEF can be applied for human alopecia.

Background: Ginsenosides are the main ingredients of Korean Red Ginseng. They have extensively been studied for their beneficial value in neurodegenerative diseases such as Parkinson's disease (PD). However, the multitarget effects of Korean Red Ginseng extract (KRGE) with various components are unclear. Methods: We investigated the multitarget activities of KRGE on neurological dysfunction and neurotoxicity in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced mouse model of PD. KRGE (37.5 mg/kg/day, 75 mg/kg/day, or 150 mg/kg/day, per os (p.o.)) was given daily before or after MPTP intoxication. Results: Pretreatment with 150 mg/kg/day KRGE produced the greatest positive effect on motor dysfunction as assessed using rotarod, pole, and nesting tests, and on the survival rate. KRGE displayed a wide therapeutic time window. These effects were related to reductions in the loss of tyrosine hydroxylase–immunoreactive dopaminergic neurons, apoptosis, microglial activation, and activation of inflammatory factors in the substantia nigra pars compacta and/or striatum after MPTP intoxication. In addition, pretreatment with KRGE activated the nuclear factor erythroid 2–related factor 2 pathways and inhibited phosphorylation of the mitogen-activated protein kinases and nuclear factor-kappa B signaling pathways, as well as blocked the alteration of blood–brain barrier integrity. Conclusion: These results suggest that KRGE may effectively reduce MPTP-induced neurotoxicity with a wide therapeutic time window through multitarget effects including antiapoptosis, antiinflammation, antioxidant, and maintenance of blood–brain barrier integrity. KRGE has potential as a multitarget drug or functional food for safe preventive and therapeutic strategies for PD. Keywords: Korean Red Ginseng extract, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Multitarget effect

Background: Depression is one of the most commonly diagnosed neuropsychiatric diseases, but the underlying mechanism and medicine are not well-known. Although Panax ginseng has been reported to exert protective effects in various neurological studies, little information is available regarding its antidepressant effects. Methods: Here, we examined the antidepressant effect and underlying mechanism of P. ginseng extract (PGE) in a chronic restraint stress (CRS)-induced depression model in mice. Results: Oral administration of PGE for 14 d decreased immobility (depression-like behaviors) time in forced swim and tail suspended tests after CRS induction, which corresponded with attenuation of the levels of serum adrenocorticotropic hormone and corticosterone, as well as attenuated c-Fos expression in the amygdala. PGE enhanced messenger RNA expression level of brain-derived neurotrophic factor but ameliorated microglial activation and neuroinflammation (the level of messenger RNA and protein expression of cyclooxygenase-2 and inducible nitric oxide synthase) in the amygdala of mice after CRS induction. Interestingly, 14-d treatment with celecoxib, a selective cyclooxygenase-2 inhibitor, and Nω-nitro-L-arginine methyl ester hydrochloride, a selective inducible nitric oxide synthase inhibitor, attenuated depression-like behaviors after CRS induction. Additionally, PGE inhibited the upregulation of the nuclear factor erythroid 2 related factor 2 and heme oxygenase-1 pathways. Conclusion: Taken together, our findings suggest that PGE exerts antidepressant-like effect of CRS-induced depression by antineuroinflammatory and antioxidant (nuclear factor erythroid 2 related factor 2/heme oxygenase-1 activation) activities by inhibiting the hypothalamo-pituitary-adrenal axis mechanism. Further studies are needed to evaluate the potential of components of P. ginseng as an alternative treatment of depression, including clinical trial evaluation.

In this paper, the hydrodynamic performance of a two-concentric-cylindrical-body WEC (Wave Energy Converter) is investigated through a systematic parametric study by using analytical solutions and model tests. The two-body WEC generates power by LEG (linear electric generator) through the relative heave motion between the inner and outer buoys. In order to maximize the relative heave motions between the two buoys, resonance of each buoy was used. As a means of finding its maximum hydrodynamic efficiency, the matched eigenfunction expansion method (MEEM) was applied to obtain the analytic solutions under the assumption of linear potential theory. The numerical results are validated through comparisons with a series of model tests conducted by authors in a 2-D wave tank at Jeju National University. Based on the case study, several design strategies that can further enhance the PTO (Power take-off) efficiency are proposed, including the optimal PTO damping and intentional mismatching of heave natural frequencies of the two buoys and the peak frequency of target wave spectrum. The intentional mismatching strategy, in particular, can increase high-quality extracted power for broader wave conditions, which is a big advantage in designing the proposed WEC-LEG system.

Liquid sloshing inside tanks of a vessel may result in increased/decreased vessel motions or structural damages. The resonant sloshing motions can be suppressed by using baffles inside a tank. Especially, more energy dissipation is possible by using porous baffles. Here, the effect of dual vertical porous baffles on the sloshing reduction inside a rectangular tank is investigated both theoretically and experimentally. The matched eigenfunction expansion method is applied to obtain the analytic solutions in the context of linear potential theory with porous boundary conditions. The porosity effect is included through inertial and quadratic-drag terms. The theoretical prediction is then compared with a series of experiments conducted by authors with harmonically oscillated rectangular tank at various frequencies and baffle parameters. The measured data reasonably correlate with the predicted values. It is found that the dual vertical porous baffles can significantly suppress sloshing motions when properly designed by selecting optimal porosity, submergence depth, and installation position.

Background Panax ginseng has been used as Korean medicine for various diseases. It has antioxidant, hypotensive, sedative, analgesic, and endocrine activities. Dammarane-type triterpenes from the plant have various beneficial effects. Methods A dammarane-type triterpene saponin was isolated from P. ginseng root through chromatography such as repeated column chromatography and medium pressure liquid chromatography. Results and conclusion New dammarane-type triterpene saponin was isolated for the first time from nature. The structure was elucidated as ginsenoside Rg12 ( 1 ) based on spectral data. There may be good materials from P. ginseng for the development of industrial applications such as nutraceutical, pharmaceutical, and cosmeceutical purposes.

The anti-sloshing effects of a vertical porous baffle placed at the center of a rolling rectangular tank have been investigated rigorously. The potential-based analytical solutions were developed using the matched eigenfunction expansion method (MEEM) with an equivalent linearized quadratic loss model. For this, the empirical formula of the drag coefficient was obtained through the curve-fitting with the CFD results for the channel flow with a circular void hole. In parallel with the analytical model, a 3D implicit turbulent model based on incompressible unsteady Reynolds-averaged Navier–Stokes (RANS) equations was used with the volume of fluid (VOF) multiphase model. To validate the analytical and numerical model, experiments were conducted in a rolling rectangular tank with a fully/partially submerged porous baffle of different porosities. The acceptability and limitation of the present analytical model was quantified and qualified using experimental and numerical approach. The presented analytical and 3D turbulent numerical model will provide a mutually complementary tool for the understanding of the energy dissipation mechanism and efficient design of the porous baffle as an anti-sloshing device.

The performance of a porous screen placed in the center of a rectangular tank has been investigated based on an analytical, numerical, and experimental approach for the lateral excitation of the tank. The two-dimensional potential model was solved analytically with the Galerkin method by adding the frictional damping coefficient at the free surface condition and considering the energy dissipation across the porous screen. The comparison of the analytical solution with the experimental results shows a good agreement for the frictional damping coefficient of 0.3. The main physical parameters are the surface elevation, pressure at the tank walls, including hydrodynamic forces on the wall, and the horizontal load on the porous screen for different submergence depths and porosities that were investigated. The presence of screen shifts the sloshing tank natural periods slightly, especially in the lowest mode. The unrevealed phenomena accompanied with linear potential theory, the nonlinear wave profile and screen associated effects were also investigated based on an experimental and numerical method. The results show that the numerical prediction with STAR-CCM+ was in good agreement with the experimental results up to second-harmonics. It was found that the porous slotted screen can be an effective device for the suppression of sloshing motion if properly designed.

The interaction between oblique incident waves and dual submerged horizontal porous plates has been investigated in the context of the two-dimensional linear potential theory including viscous effect through Darcy's law. The matched eigenfunction expansion method(MEFEM) for multiple domains is applied to obtain the analytic solutions. The analytic solutions are verified through comparisons with the independently developed multi-domain BEM(boundary element method) solutions based on simple-sources (second-kind modified Bessel function). The BEM solutions are further used for more general cases including inclined porous plates. Both analytical and BEM solutions are also verified against a series of experiments conducted in a two-dimensional glass-walled wave tank at Jeju National University. In the comparison, the empirical relationship between the plate porosity and porous parameter obtained by Cho and Kim (2008) was successfully applied. The dependence of the reflected and transmitted coefficients on the design parameters, such as porosity, submergence depth, plate width, gap distance, wave heading, inclined angle of the plate, and wave length, is systematically analyzed. It is found that the performance of the proposed dual submerged horizontal porous plates can be significantly enhanced by selecting optimal design parameters for the given wave condition. The upper porous plate plays a major role in wave blocking performance but the presence of lower porous plate may be important when tidal variation is large.

Ethnopharmacological relevance Rhizoma coptidis (RC) has been used as a remedy for inflammation-related diseases in traditional medicine. Although it is known to have anti-inflammatory activities, its mechanism of action on lipopolysaccharide (LPS)-induced inflammation has not yet been identified in detail. Aim of the study This study was designed to assess the beneficial effects of pretreatment with RC in ameliorating LPS-induced liver inflammation. Materials and methods Mice were orally administered RC (500, 1000 mg/kg) for three days in a row. 1 h after the last RC administration, the mice were intraperitoneally injected with LPS (35 mg/kg). After treatment, histological alterations and inflammatory factor levels in the liver and proinflammatory cytokines in the serum associated with inflammation were examined. Results We found that pretreatment with RC (500 and 1000 mg/kg) exerted a significant protective effect by attenuating liver histopathological changes in endotoxemic mice. The results also demonstrated that RC suppressed secretion of LPS-stimulated pro-inflammatory cytokines, such as interleukin-6 (IL-6). Furthermore, RC inhibited LPS-mediated nuclear factor (NF)-κB activation via the prevention of IκB-α phosphorylation, as well as the phosphorylation of ERK1/2, JNK, and p38 MAPKs. These results were associated with decreases in the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (I-NOS). Conclusions The results presented here clearly demonstrate that RC could significantly protect mice against LPS-induced acute liver injury.

The interaction of oblique monochromatic incident waves with a submerged horizontal porous plate has been investigated in the context of two-dimensional linear potential theory. The matched eigenfunction expansion method is applied to obtain the analytic solution. The present formulations, suggested by Molin and Nielsen (2004) and Liu and Li (2011) , are compared with the independent solutions using complex dispersion relations and they are proved to be identical. The former approach, however, may be more straightforwardly extended to the case of multi-layer horizontal porous plates. Also, the present predictions are compared with a series of experiments conducted in a two-dimensional wave tank at Jeju National University. By using the empirical relationship between plate porosity and porous parameter obtained by authors ( Cho and Kim, 2008 ), the measured reflection and transmission coefficients reasonably follow the trend of predicted values. The performance of the proposed submerged horizontal porous breakwaters can be significantly enhanced by selecting optimal design parameters, such as porosity, submergence depth, and plate width. The optimal cases are obtained through a systematic parametric study, which illustrates the usefulness of the presently developed analytic solutions.

Ginseng, the root of the Panax ginseng, has been a popular and widely-used traditional herbal medicine in Korea, China, and Japan for thousands of years. Now it has become popular as a functional health food and is used globally as a natural medicine. Evidence is accumulating in the literature on the physiological and pharmacological effects of P. ginseng on neurodegenerative diseases. Possible ginseng- or ginsenosides-mediated neuroprotective mechanisms mainly involve maintaining homeostasis, and anti-inflammatory, anti-oxidant, anti-apoptotic, and immune-stimulatory activities. This review considers publications dealing with the various actions of P. ginseng that are indicative of possible neurotherapeutic efficacies in neurodegenerative diseases and neurological disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis and multiple sclerosis.

This study was to investigate the effects of ascorbic acid on the hippocampus of suckling rats in the presence of lead (Pb)-induced oxidative stress. Pregnant Sprague-Dawley rats received treatment with drinking water, divided into three groups, as follows: (1) distilled water; (2) 0.2% Pb; (3) 0.2% Pb+ascorbic acid (100mg/kg/day). Rat pups were euthanized at the age of 21days and their brain tissue was examined using light microscopy. Protein levels of Cu/Zn superoxide dismutase (Cu/Zn SOD), manganese superoxide dismutase (Mn SOD), and catalase (CAT) in the hippocampus were determined by Western blotting. We found a significant decrease in levels of Cu/Zn SOD and Mn SOD among Pb-exposed pups. Ascorbic acid supplementation appeared to negate the decrease in protein levels for Cu/Zn SOD and Mn SOD. In the case of CAT, there was no effect from Pb administration alone and Pb plus ascorbic acid appeared to increase the levels. In histopathology, ascorbic acid decreased the number of damaged cells in cornu ammonis areas CA1, CA3, and the dentate gyrus (DG) in hippocampus. Our results showed that administration of ascorbic acid during pregnancy and lactation could ameliorate some of the oxidative damage induced by Pb exposure in the developing rat hippocampus.

We have recently demonstrated that inferior alveolar nerve and mental nerve (branches of the mandibular nerve) injury from rats serves as a valid trigeminal neuropathic pain model. In these animals, we found that neuronal loss of trigeminal ganglion (TG) was not correlated with pain hypersensitivity. In this study, we examined changes of transient receptor potential vanilloid 1 (TRPV1) expression in the injured and uninjured TG neurons using immunohistochemical analysis at 3 days after surgery, the time point where we observed significant pain hypersensitivity. Injured neurons were identified by positive immunoreactivity for activating transcription factor 3 (ATF3). ATF3 immunoreactivity was exclusively observed in the nuclei of subpopulation of ipsilateral mandibular TG neurons, whereas no ATF3 expression was found in the naive and contralateral TG neurons. Interestingly, the expression of TRPV1 was increased in the uninjured ipsilateral maxillary TG neurons as well as in the uninjured ipsilateral mandibular TG neurons. The upregulation of TRPV1 and ATF3 expression returned to the basal level at 60 days after surgery. Our results demonstrate that trigeminal sensory nerve injury induced differential changes in TRPV1 expression of the injured and uninjured TG neurons. The upregulation of TRPV1 in uninjured TG neurons may play an important role in pain hypersensitivity after trigeminal nerve injury. Perspective The TRPV1 is a well-known pain transducer molecule and plays crucial roles in the perception of inflammatory and thermal pain. This article presents that TRPV1 expression was increased in uninjured neurons rather than injured neurons after peripheral nerve injury. The upregulation of TRPV1 in uninjured neurons may be associated with the development of neuropathic pain. TRPV1 might be a potential target for the treatment of neuropathic pain.

Traumatic brain injury is accompanied by glial cell activation around the site of the injury. In this study, we investigated the role of toll-like receptor 2 (TLR2) in glial cell activation using a stab-wound injury (SWI) model with TLR2 knock-out mice. Penetration of a normal mouse brain with a 26-G needle using a stereotaxic instrument resulted in an 18- and 4-fold upregulation of GFAP and CD11b mRNA, respectively, along the needle track in the injury area. However, in the TLR2 knock-out mice, the induced expression of these genes was reduced by 70% and 40%, respectively. Likewise, there was a reduction in the area of activated glial cells detected by immunohistochemistry and the glial cells had a less-activated morphology in the TLR2 knock-out mice. In addition, the expression of the heme oxygenase-1 (HO-1) gene, a glia-expressing wound-responsive gene, was reduced after SWI in TLR2 knock-out mice. Taken together, these data argue that TLR2 contributes to the glial cell activation and HO-1 gene expression associated with traumatic brain injury.