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1.
Molecules ; 26(20)2021 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-34684879

RESUMEN

Ginseng-derived gintonin reportedly contains functional lysophosphatidic acids (LPAs) as LPA receptor ligands. The effect of the gintonin-enriched fraction (GEF) on in vitro and in vivo glucagon-like protein-1 (GLP-1) secretion, which is known to stimulate insulin secretion, via LPA receptor(s) remains unclear. Accordingly, we examined the effects of GEF on GLP-1 secretion using human enteroendocrine NCI-H716 cells. The expression of several of LPA receptor subtypes in NCI-H716 cells using qPCR and Western blotting was examined. LPA receptor subtype expression was in the following order: LPA6 > LPA2 > LPA4 > LPA5 > LPA1 (qPCR), and LPA6 > LPA4 > LPA2 > LPA1 > LPA3 > LPA5 (Western blotting). GEF-stimulated GLP-1 secretion occurred in a dose- and time-dependent manner, which was suppressed by cAMP-Rp, a cAMP antagonist, but not by U73122, a phospholipase C inhibitor. Furthermore, silencing the human LPA6 receptor attenuated GEF-mediated GLP-1 secretion. In mice, low-dose GEF (50 mg/kg, peroral) increased serum GLP-1 levels; this effect was not blocked by Ki16425 co-treatment. Our findings indicate that GEF-induced GLP-1 secretion could be achieved via LPA6 receptor activation through the cAMP pathway. Hence, GEF-induced GLP secretion via LPA6 receptor regulation might be responsible for its beneficial effects on human endocrine physiology.


Asunto(s)
Neoplasias Colorrectales/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Panax/química , Extractos Vegetales/farmacología , Animales , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Glucagón/metabolismo , Humanos , Secreción de Insulina , Lisofosfolípidos , Masculino , Ratones , Ratones Endogámicos ICR , Receptores del Ácido Lisofosfatídico/genética , Receptores del Ácido Lisofosfatídico/metabolismo , Transducción de Señal , Células Tumorales Cultivadas
2.
Int J Mol Sci ; 22(18)2021 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-34576317

RESUMEN

Gintonin, a novel compound of ginseng, is a ligand of the lysophosphatidic acid (LPA) receptor. The in vitro and in vivo skin wound healing effects of gintonin remain unknown. Therefore, the objective of this study was to investigate the effects of gintonin on wound healing-linked responses, especially migration and proliferation, in skin keratinocytes HaCaT. In this study, 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide assay, Boyden chamber migration assay, scratch wound healing assay, and Western blot assay were performed. A tail wound mouse model was used for the in vivo test. Gintonin increased proliferation, migration, and scratch closure in HaCaT cells. It also increased the release of vascular endothelial growth factor (VEGF) in HaCaT cells. However, these increases, induced by gintonin, were markedly blocked by treatment with Ki16425, an LPA inhibitor, PD98059, an ERK inhibitor, 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxymethyl ester), a calcium chelator, and U73122, a PLC inhibitor. The VEGF receptor inhibitor axitinib also attenuated gintonin-enhanced HaCaT cell proliferation. Gintonin increased the phosphorylation of AKT and ERK1/2 in HaCaT cells. In addition, gintonin improved tail wound healing in mice. These results indicate that gintonin may promote wound healing through LPA receptor activation and/or VEGF release-mediated downstream signaling pathways. Thus, gintonin could be a beneficial substance to facilitate skin wound healing.


Asunto(s)
Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Extractos Vegetales/farmacología , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Panax/química , Transducción de Señal/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos
3.
Molecules ; 26(14)2021 Jul 07.
Artículo en Inglés | MEDLINE | ID: mdl-34299412

RESUMEN

Gintonin is a kind of ginseng-derived glycolipoprotein that acts as an exogenous LPA receptor ligand. Gintonin has in vitro and in vivo neuroprotective effects; however, little is known about the cellular mechanisms underlying the neuroprotection. In the present study, we aimed to clarify how gintonin attenuates iodoacetic acid (IAA)-induced oxidative stress. The mouse hippocampal cell line HT22 was used. Gintonin treatment significantly attenuated IAA-induced reactive oxygen species (ROS) overproduction, ATP depletion, and cell death. However, treatment with Ki16425, an LPA1/3 receptor antagonist, suppressed the neuroprotective effects of gintonin. Gintonin elicited [Ca2⁺]i transients in HT22 cells. Gintonin-mediated [Ca2⁺]i transients through the LPA1 receptor-PLC-IP3 signaling pathway were coupled to increase both the expression and release of BDNF. The released BDNF activated the TrkB receptor. Induction of TrkB phosphorylation was further linked to Akt activation. Phosphorylated Akt reduced IAA-induced oxidative stress and increased cell survival. Our results indicate that gintonin attenuated IAA-induced oxidative stress in neuronal cells by activating the LPA1 receptor-BDNF-TrkB-Akt signaling pathway. One of the gintonin-mediated neuroprotective effects may be achieved via anti-oxidative stress in nervous systems.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hipocampo/efectos de los fármacos , Neuronas/efectos de los fármacos , Extractos Vegetales/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores del Ácido Lisofosfatídico/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Supervivencia Celular , Hipocampo/metabolismo , Hipocampo/patología , Ratones , Neuronas/metabolismo , Neuronas/patología , Fármacos Neuroprotectores/farmacología , Proteínas Proto-Oncogénicas c-akt/genética , Receptores del Ácido Lisofosfatídico/genética , Transducción de Señal
4.
J Ginseng Res ; 45(2): 264-272, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33841007

RESUMEN

BACKGROUND: Gintonin is a ginseng-derived exogenous G-protein-coupled lysophosphatidic acid (LPA) receptor ligand, which exhibits in vitro and in vivo functions against Alzheimer disease (AD) through lysophosphatidic acid 1/3 receptors. A recent study demonstrated that systemic treatment with gintonin enhances paracellular permeability of the blood-brain barrier (BBB) through the LPA1/3 receptor. However, little is known about whether gintonin can enhance brain delivery of donepezil (DPZ) (Aricept), which is a representative cognition-improving drug used in AD clinics. In the present study, we examined whether systemic administration of gintonin can stimulate brain delivery of DPZ. METHODS: We administered gintonin and DPZ alone or coadministered gintonin with DPZ intravenously or orally to rats. Then we collected the cerebral spinal fluid (CSF) and serum and determined the DPZ concentration through liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. RESULTS: Intravenous, but not oral, coadministration of gintonin with DPZ increased the CSF concentration of DPZ in a concentration- and time-dependent manner. Gintonin-mediated enhancement of brain delivery of DPZ was blocked by Ki16425, a LPA1/3 receptor antagonist. Coadministration of vascular endothelial growth factor (VEGF) + gintonin with DPZ similarly increased CSF DPZ concentration. However, gintonin-mediated enhancement of brain delivery of DPZ was blocked by axitinip, a VEGF receptor antagonist. Mannitol, a BBB disrupting agent that increases the BBB permeability, enhanced gintonin-mediated enhancement of brain delivery of DPZ. CONCLUSIONS: We found that intravenous, but not oral, coadministration of gintonin facilitates brain delivery of DPZ from plasma via LPA1/3 and VEGF receptors. Gintonin is a potential candidate as a ginseng-derived novel agent for the brain delivery of DPZ for treatment of patients with AD.

5.
Integr Med Res ; 10(2): 100475, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33134079

RESUMEN

BACKGROUND: Recently, gintonin and gintonin-enriched fraction (GEF) have been isolated from ginseng, a herbal medicine. Gintonin induces [Ca2+]i transition in cultured hippocampal neurons and stimulates acetylcholine release through LPA receptor activation. Oral administration of GEF is linked to hippocampus-dependent cognitive enhancement and other neuroprotective effects; however, effects of its long-term administration on hippocampal gene expression remains unknown. Here, we used next-generation sequence (NGS) analysis to examine changes in hippocampal gene expressions after long-term oral administration of GEF. METHODS: C57BL/6 mice were divided into three groups: control group, GEF50 (GEF 50 mg/kg, p.o.), and GEF100 (GEF 100 mg/kg, p.o.). After 22 days, total RNA was extracted from mouse hippocampal tissues. NGS was used for gene expression profiling; quantitative-real-time PCR and western blot were performed to quantify the changes in specific genes and to confirm the protein expression levels in treatment groups. RESULTS: NGS analysis screened a total of 23,282 genes, analyzing 11-related categories. We focused on the neurogenesis category, which includes four genes for candidate markers: choline acetyltransferase (ChAT) gene, ß3-adrenergic receptor (Adrb3) gene, and corticotrophin-releasing hormone (Crh) gene, and tryptophan 2,3-dioxygenase (Tdo2) gene. Real-time PCR showed a marked overexpression of ChAT, Adrb3, and Crh genes, while reduced expression of Tdo2. Western blot analysis also confirmed increased ChAT and decreased Tdo2 protein levels. CONCLUSION: We found that GEF affects mouse hippocampal gene expressions, associated with memory, cognitive, anti-stress and anti-anxiety functions, and neurodegeneration at differential degree, that might explain the genetic bases of GEF-mediated neuroprotective effects.

6.
Biomolecules ; 10(7)2020 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-32679738

RESUMEN

Obesity is a major health concern and is becoming an increasingly serious societal problem worldwide. The browning of white adipocytes has received considerable attention because of its potential protective effect against obesity-related metabolic disease. The gintonin-enriched fraction (GEF) is a non-saponin, glycolipoprotein component of ginseng that is known to have neuroprotective and anti-inflammatory effects. However, the anti-obesity and browning effects of GEF have not been explored to date. Therefore, we aimed to determine whether GEF has a preventive effect against obesity. We differentiated 3T3-L1 cells and mouse primary subcutaneous adipocytes for 8 days in the presence or absence of GEF, and then measured the expression of intermediates in signaling pathways that regulate triglyceride (TG) synthesis and browning by Western blotting and immunofluorescence analysis. We found that GEF reduced lipid accumulation by reducing the expression of pro-adipogenic and lipogenic factors, and increased lipolysis and thermogenesis, which may be mediated by an increase in the phosphorylation of protein kinase A. These findings suggest that GEF may induce fat metabolism and energy expenditure in white adipocytes and therefore may represent a potential treatment for obesity.


Asunto(s)
Adipocitos Marrones/metabolismo , Adipogénesis/efectos de los fármacos , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Panax/química , Extractos Vegetales/farmacología , Células 3T3-L1 , Adipocitos Blancos/efectos de los fármacos , Adipocitos Blancos/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , AMP Cíclico/metabolismo , Metabolismo Energético , Ratones , Fosforilación/efectos de los fármacos , Extractos Vegetales/química , Transducción de Señal/efectos de los fármacos
7.
Biomolecules ; 10(3)2020 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-32131481

RESUMEN

Gintonin, a novel ginseng-derived lysophosphatidic acid receptor ligand, improves brain functions and protects neurons from oxidative stress. However, little is known about the effects of gintonin against Pb-induced brain maldevelopment. We investigated the protective effects of gintonin on the developing cerebellum after prenatal and postnatal Pb exposure. Pregnant female rats were randomly divided into three groups: control, Pb (0.3% Pb acetate in drinking water), and Pb plus gintonin (100 mg/kg, p.o.). Blood Pb was increased in dams and pups; gintonin treatment significantly decreased blood Pb. On postnatal day 21, the number of degenerating Purkinje cells was remarkably increased while the number of calbindin-, GAD67-, NMDAR1-, LPAR1-immunoreactive intact Purkinje cells, and GABA transporter 1-immunoreactive pinceau structures were significantly reduced in Pb-exposed offspring. Following Pb exposure, gintonin ameliorated cerebellar degenerative effects, restored increased pro-apoptotic Bax, and decreased anti-apoptotic Bcl2. Gintonin treatment attenuated Pb-induced accumulation of oxidative stress (Nrf2 and Mn-SOD) and inflammation (IL-1ß and TNFα,), restoring the decreased cerebellar BDNF and Sirt1. Gintonin ameliorated Pb-induced impairment of myelin basic protein-immunoreactive myelinated fibers of Purkinje cells. Gintonin attenuated Pb-induced locomotor dysfunctions. The present study revealed the ameliorating effects of gintonin against Pb, suggesting the potential use of gintonin as a preventive agent in Pb poisoning during pregnancy and lactation.


Asunto(s)
Lactancia/metabolismo , Intoxicación por Plomo , Exposición Materna/efectos adversos , Panax/química , Extractos Vegetales/farmacología , Células de Purkinje/metabolismo , Animales , Femenino , Intoxicación por Plomo/tratamiento farmacológico , Intoxicación por Plomo/embriología , Intoxicación por Plomo/patología , Extractos Vegetales/química , Embarazo , Células de Purkinje/patología , Ratas
8.
Molecules ; 25(5)2020 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-32121640

RESUMEN

Gintonin, a novel ginseng-derived glycolipoprotein complex, has an exogenous ligand for lysophosphatidic acid (LPA) receptors. However, recent lipid analysis of gintonin has shown that gintonin also contains other bioactive lipids besides LPAs, including linoleic acid and lysophosphatidylinositol (LPI). Linoleic acid, a free fatty acid, and LPI are known as ligands for the G-protein coupled receptors (GPCR), GPR40, and GPR55, respectively. We, herein, investigated whether gintonin could serve as a ligand for GPR40 and GPR55, using the insulin-secreting beta cell-derived cell line INS-1 and the human prostate cancer cell line PC-3, respectively. Gintonin dose-dependently enhanced insulin secretion from INS-1 cells. Gintonin-stimulated insulin secretion was partially inhibited by a GPR40 receptor antagonist but not an LPA1/3 receptor antagonist and was down-regulated by small interfering RNA (siRNA) against GPR40. Gintonin dose-dependently induced [Ca2+]i transients and Ca2+-dependent cell migration in PC-3 cells. Gintonin actions in PC-3 cells were attenuated by pretreatment with a GPR55 antagonist and an LPA1/3 receptor antagonist or by down-regulating GPR55 with siRNA. Taken together, these results demonstrated that gintonin-mediated insulin secretion by INS-1 cells and PC-3 cell migration were regulated by the respective activation of GPR40 and GPR55 receptors. These findings indicated that gintonin could function as a ligand for both receptors. Finally, we demonstrated that gintonin contained two more GPCR ligands, in addition to that for LPA receptors. Gintonin, with its multiple GPCR ligands, might provide the molecular basis for the multiple pharmacological actions of ginseng.


Asunto(s)
Panax/química , Extractos Vegetales/farmacología , Receptores de Cannabinoides , Receptores Acoplados a Proteínas G/agonistas , Animales , Señalización del Calcio/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Secreción de Insulina/efectos de los fármacos , Ligandos , Células PC-3 , Extractos Vegetales/química , Ratas , Receptores de Cannabinoides/metabolismo , Receptores Acoplados a Proteínas G/metabolismo
9.
Molecules ; 25(5)2020 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-32106493

RESUMEN

Heat stress can be caused by various environmental factors. When exposed to heat stress, oxidative stress and inflammatory reaction occur due to an increase of reactive oxygen species (ROS) in the body. In particular, inflammatory responses induced by heat stress are common in muscle cells, which are the most exposed to heat stress and directly affected. Gintonin-Enriched Fraction (GEF) is a non-saponin component of ginseng, a glycolipoprotein. It is known that it has excellent neuroprotective effects, therefore, we aimed to confirm the protective effect against heat stress by using GEF. C2C12 cells were exposed to high temperature stress for 1, 12 and 15 h, and the expression of signals was analyzed over time. Changes in the expression of the factors that were observed under heat stress were confirmed at the protein level. Exposure to heat stress increases phosphorylation of p38 and extracellular signal-regulated kinase (ERK) and increases expression of inflammatory factors such as NLRP3 inflammasome through lysophosphatidic acid (LPA) receptor. Activated inflammatory signals also increase the secretion of inflammatory cytokines such as interleukin 6 (IL-6) and interleukin 18 (IL-18). Also, expression of glutathione reductase (GR) and catalase related to oxidative stress is increased. However, it was confirmed that the changes due to the heat stress were suppressed by the GEF treatment. Therefore, we suggest that GEF helps to protect heat stress in muscle cell and prevent tissue damage by oxidative stress and inflammation.


Asunto(s)
Inflamación/tratamiento farmacológico , Panax/química , Extractos Vegetales/farmacología , Receptores del Ácido Lisofosfatídico/genética , Animales , Calcio/metabolismo , Línea Celular , Respuesta al Choque Térmico/efectos de los fármacos , Respuesta al Choque Térmico/fisiología , Humanos , Ratones , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/química , Especies Reactivas de Oxígeno/metabolismo
10.
Artículo en Inglés | MEDLINE | ID: mdl-32013120

RESUMEN

Gintonin is a newly discovered ingredient of ginseng and plays an exogenous ligand for G protein-coupled lysophosphatidic acid receptors. We previously showed that gintonin exhibits diverse effects from neurotransmitter release to improvement of Alzheimer's disease-related cognitive dysfunctions. However, previous studies did not show whether gintonin has protective effects against environmental heavy metal. We investigated the effects of gintonin-enriched fraction (GEF) on methylmercury (MeHg)-induced neurotoxicity and learning and memory dysfunction and on organ MeHg elimination. Using hippocampal neural progenitor cells (hNPCs) and mice we examined the effects of GEF on MeHg-induced hippocampal NPC neurotoxicity, on formation of reactive oxygen species (ROS), and on in vivo learning and memory functions after acute MeHg exposure. Treatment of GEF to hNPCs attenuated MeHg-induced neurotoxicity with concentration- and time-dependent manner. GEF treatment inhibited MeHg- and ROS inducer-induced ROS formations. Long-term treatment of GEF also improved MeHg-induced learning and memory dysfunctions. Oral administration of GEF decreased the concentrations of MeHg in blood, brain, liver, and kidney. This is the first report that GEF attenuated MeHg-induced in vitro and in vivo neurotoxicities through LPA (lysophosphatidic acids) receptor-independent manner and increased organ MeHg elimination. GEF-mediated neuroprotection might achieve via inhibition of ROS formation and facilitation of MeHg elimination from body.


Asunto(s)
Disfunción Cognitiva/tratamiento farmacológico , Compuestos de Metilmercurio/toxicidad , Panax/química , Extractos Vegetales/uso terapéutico , Animales , Disfunción Cognitiva/inducido químicamente , Femenino , Ratones , Ratones Endogámicos C57BL , Receptores del Ácido Lisofosfatídico
11.
J Ginseng Res ; 43(2): 209-217, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30962735

RESUMEN

BACKGROUND: Ginseng is a traditional herbal medicine for human health. Ginseng contains a bioactive ligand named gintonin. The active ingredient of gintonin is lysophosphatidic acid C18:2 (LPA C18:2). We previously developed a method for gintonin-enriched fraction (GEF) preparation to mass-produce gintonin from ginseng. However, previous studies did not show the presence of other bioactive lipids besides LPAs. The aim of this study was to quantify the fatty acids, lysophospholipids (LPLs), and phospholipids (PLs) besides LPAs in GEF. METHODS: We prepared GEF from white ginseng. We used gas chromatography-mass spectrometry for fatty acid analysis and liquid chromatography-tandem mass spectrometry for PL analysis, and quantified the fatty acids, LPLs, and PLs in GEF using respective standards. We examined the effect of GEF on insulin secretion in INS-1 cells. RESULTS: GEF contains about 7.5% linoleic (C18:2), 2.8% palmitic (C16:0), and 1.5% oleic acids (C18:1). GEF contains about 0.2% LPA C18:2, 0.06% LPA C16:0, and 0.02% LPA C18:1. GEF contains 0.08% lysophosphatidylcholine, 0.03% lysophosphatidylethanolamine, and 0.13% lysophosphatidylinositols. GEF also contains about 1% phosphatidic acid (PA) 16:0-18:2, 0.5% PA 18:2-18:2, and 0.2% PA 16:0-18:1. GEF-mediated insulin secretion was not blocked by LPA receptor antagonist. CONCLUSION: We determined four characteristics of GEF through lipid analysis and insulin secretion. First, GEF contains a large amount of linoleic acid (C18:2), PA 16:0-18:2, and LPA C18:2 compared with other lipids. Second, the main fatty acid component of LPLs and PLs is linoleic acid (C18:2). Third, GEF stimulates insulin secretion not through LPA receptors. Finally, GEF contains bioactive lipids besides LPAs.

12.
Nutrients ; 11(1)2019 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-30650605

RESUMEN

Ascorbic acid is essential for normal brain development and homeostasis. However, the effect of ascorbic acid on adult brain aging has not been determined. Long-term treatment with high levels of D-galactose (D-gal) induces brain aging by accumulated oxidative stress. In the present study, mice were subcutaneously administered with D-gal (150 mg/kg/day) for 10 weeks; from the seventh week, ascorbic acid (150 mg/kg/day) was orally co-administered for four weeks. Although D-gal administration alone reduced hippocampal neurogenesis and cognitive functions, co-treatment of ascorbic acid with D-gal effectively prevented D-gal-induced reduced hippocampal neurogenesis through improved cellular proliferation, neuronal differentiation, and neuronal maturation. Long-term D-gal treatment also reduced expression levels of synaptic plasticity-related markers, i.e., synaptophysin and phosphorylated Ca2+/calmodulin-dependent protein kinase II, while ascorbic acid prevented the reduction in the hippocampus. Furthermore, ascorbic acid ameliorated D-gal-induced downregulation of superoxide dismutase 1 and 2, sirtuin1, caveolin-1, and brain-derived neurotrophic factor and upregulation of interleukin 1 beta and tumor necrosis factor alpha in the hippocampus. Ascorbic acid-mediated hippocampal restoration from D-gal-induced impairment was associated with an enhanced hippocampus-dependent memory function. Therefore, ascorbic acid ameliorates D-gal-induced impairments through anti-oxidative and anti-inflammatory effects, and it could be an effective dietary supplement against adult brain aging.


Asunto(s)
Envejecimiento , Ácido Ascórbico/farmacología , Encéfalo/efectos de los fármacos , Galactosa/efectos adversos , Memoria/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Plasticidad Neuronal , Animales , Antiinflamatorios/farmacología , Antioxidantes/metabolismo , Antioxidantes/farmacología , Encéfalo/citología , Encéfalo/metabolismo , Encéfalo/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Calcio/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Caveolina 1/metabolismo , Hipocampo/patología , Interleucina-1beta/metabolismo , Masculino , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/patología , Trastornos de la Memoria/prevención & control , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Sirtuina 1/metabolismo , Sinaptofisina/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
13.
Mol Neurobiol ; 56(5): 3280-3294, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30117105

RESUMEN

Astrocytes are a unique brain cell-storing glycogen and express lysophosphatidic acid (LPA) receptors. Gintonin is a ginseng-derived exogenous G protein-coupled LPA receptor ligand. Accumulating evidence shows that astrocytes serve as an energy supplier to neurons through astrocytic glycogenolysis under physiological and pathophysiological conditions. However, little is known about the relationships between LPA receptors and astrocytic glycogenolysis or about the roles of LPA receptors in hypoxia and re-oxygenation stresses. In the present study, we examined the functions of gintonin-mediated astrocytic glycogenolysis in adenosine triphosphate (ATP) production, glutamate uptake, and cell viability under normoxic, hypoxic, and re-oxygenation conditions. The application of gintonin or LPA to astrocytes induced glycogenolysis in concentration- and time-dependent manners. The stimulation of gintonin-mediated astrocytic glycogenolysis was achieved through the LPA receptor-Gαq/11 protein-phospholipase C-inositol 1,4,5-trisphosphate receptor-intracellular calcium ([Ca2+]i) transient pathway. Gintonin treatment to astrocytes increased the phosphorylation of brain phosphorylase kinase, with sensitive manner to K252a, an inhibitor of phosphorylase kinase. Gintonin-mediated astrocytic glycogenolysis was blocked by isofagomine, a glycogen phosphorylase inhibitor. Gintonin additionally increased astrocytic glycogenolysis under hypoxic and re-oxygenation conditions. Moreover, gintonin increased ATP production, glutamate uptake, and cell viability under the hypoxic and re-oxygenation conditions. Collectively, we found that the gintonin-mediated [Ca2+]i transients regulated by LPA receptors were coupled to astrocytic glycogenolysis and that stimulation of gintonin-mediated astrocytic glycogenolysis was coupled to ATP production and glutamate uptake under hypoxic and re-oxygenation conditions, ultimately protecting astrocytes. Hence, the gintonin-mediated astrocytic energy that is modulated via LPA receptors helps to protect astrocytes under hypoxia and re-oxygenation stresses.


Asunto(s)
Astrocitos/metabolismo , Astrocitos/patología , Glucogenólisis/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Oxígeno/farmacología , Panax/química , Receptores del Ácido Lisofosfatídico/metabolismo , Estrés Fisiológico , Adenosina Trifosfato/biosíntesis , Animales , Astrocitos/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Inhibidores Enzimáticos/farmacología , Ácido Glutámico/metabolismo , Glucógeno Sintasa/metabolismo , Ligandos , Lisofosfolípidos/farmacología , Ratones , Modelos Biológicos , Transducción de Señal/efectos de los fármacos , Estrés Fisiológico/efectos de los fármacos
14.
Gerontology ; 64(6): 562-575, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30138913

RESUMEN

BACKGROUND: Ginseng has been used to improve brain function and increase longevity. However, little is known about the ingredients of ginseng and molecular mechanisms of its anti-brain aging effects. Gintonin is a novel exogenous ginseng-derived lysophosphatidic acid (LPA) receptor ligand; LPA and LPA1 receptors are involved in adult hippocampal neurogenesis. D-galactose (D-gal) is used to induce brain -aging in animal models because long-term treatment with D-gal facilitates hippocampal aging in experimental adult animals by decreasing hippocampal neurogenesis and inducing learning and memory dysfunction. OBJECTIVE: To investigate the protective effects of gintonin on D-gal-induced hippocampal senescence, impairment of long-term potentiation (LTP), and memory dysfunction. METHODS: Brain hippocampal aging was induced by D-gal administration (150 mg/kg/day, s.c.; 10 weeks). From the 7th week, gintonin (50 or 100 mg/kg/day, per os) was co-administered with D-gal for 4 weeks. We performed histological analyses, LTP measurements, and object location test. RESULTS: Co-administration of gintonin ameliorated D-gal-induced reductions in hippocampal Ki67-immunoreactive proliferating cells, doublecortin-immunoreactive neuroblasts, 5-bromo-2'-deoxyuridine-incorporating NeuN-immunoreactive mature neurons, and LPA1 receptor expression. Co-administration of gintonin in D-gal-treated mice increased the expression of phosphorylated cyclic adenosine monophosphate response element binding protein in the hippocampal dentate gyrus. In addition, co-administration of gintonin in D-gal-treated mice enhanced LTP and restored the cognitive functions compared with those in mice treated with D-gal only. CONCLUSION: These results show that gintonin administration restores D-gal-induced memory deficits by enhancing hippocampal LPA1 receptor expression, LTP, and neurogenesis. Finally, the present study shows that gintonin exerts anti-brain aging effects that are responsible for alleviating brain aging-related dysfunction.


Asunto(s)
Senescencia Celular , Galactosa/metabolismo , Hipocampo , Potenciación a Largo Plazo/efectos de los fármacos , Trastornos de la Memoria , Extractos Vegetales/farmacología , Animales , Senescencia Celular/efectos de los fármacos , Senescencia Celular/fisiología , Modelos Animales de Enfermedad , Glicoproteínas/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Lisofosfolípidos/farmacología , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/fisiopatología , Ratones , Neurogénesis/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/fisiología , Receptores del Ácido Lisofosfatídico/metabolismo , Resultado del Tratamiento
15.
Int J Biol Macromol ; 114: 1325-1337, 2018 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-29604355

RESUMEN

Gintonin is a ginseng-derived G-protein-coupled lysophosphatidic acid (LPA) receptor ligand. Gintonin induces [Ca2+]i transient and biological effects through LPA receptor and increases the permeability of the blood-brain barrier (BBB). However, little is known about its mechanisms on the BBB. We examined the in vitro effects of gintonin using primary human brain microvascular endothelial cells (HBMECs) and the in vivo effects of gintonin on brain delivery. Fluorescent-labeled gintonin bound to HBMECs and co-localized with the LPA1 receptor. Gintonin caused morphological changes, increased junctional spaces, and induced differential effects on junctional protein levels such as vascular endothelial-cadherin, occludin, zonula occludens 1, and claudin-5, in HBMECs. Gintonin led to the opening of gap junctions between HBMECs, and allowed Texas red-dextran to enter the cells, which was blocked by Ki16425, an LPA1/3 receptor antagonist, and Y27632, a Rho-associated kinase inhibitor. Intravenous administration of gintonin in rodents also increased the delivery of fluorescein isothiocyanate-dextran or erythropoietin to the brain. Furthermore, fluorescent-labeled gintonin bound to endothelial cells, neurons, and glia in the brain following its entry. Our findings show that gintonin facilitates entry to the brain through the paracellular pathway. Thus, gintonin may be an herbal medicine-derived candidate to overcome the BBB in drug delivery.


Asunto(s)
Barrera Hematoencefálica/metabolismo , Sistemas de Liberación de Medicamentos , Panax/química , Extractos Vegetales , Receptores del Ácido Lisofosfatídico/agonistas , Animales , Células Cultivadas , Humanos , Masculino , Ratones , Permeabilidad , Extractos Vegetales/química , Extractos Vegetales/farmacocinética , Extractos Vegetales/farmacología , Ratas Sprague-Dawley , Receptores del Ácido Lisofosfatídico/metabolismo
17.
Biol Pharm Bull ; 40(7): 1063-1070, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28674249

RESUMEN

Ginseng extract has been used for prevention of atopic dermatitis (AD) in experimental animal models. However, little is known about its active ingredients and the molecular mechanisms underlying its anti-AD effects. Recently, we isolated a unique lysophosphatidic acid (LPA) receptor ligand, gintonin, from ginseng. Gintonin, the glycolipoprotein fraction of ginseng, contains LPAs, mainly LPA C18 : 2 with other minor lysophospholipid components. A line of evidence showed that serum autotaxin (ATX) activity and level are significantly elevated in human AD patients compared to those in normal controls, which indicates that ATX may be involved in human AD. In a previous study, we demonstrated that gintonin exerted anti-inflammatory effects via inhibition of microglial activation and proinflammatory cytokine production by immune cells and that it strongly inhibited ATX activity. In this study, we investigated whether oral administration of the gintonin-enriched fraction (GEF) could ameliorate the symptoms of 2,4-dinitrofluorobenzene (DNFB)-induced AD in NC/Nga mice. We found that oral administration of GEF to DNFB-induced AD mice for 2 weeks reduced ear swelling and AD skin index. In addition, oral administration of GEF reduced the serum levels of immunoglobulin E, histamine, interleukin-4, and interferon-γ. Histological examination showed that oral administration of GEF attenuated skin inflammation and significantly reduced eosinophil and mast cell infiltration into the skin. Moreover, oral administration of GEF not only decreased serum ATX level but also reduced serum ATX activity. The present study shows that the anti-AD effects of ginseng might be attributed to GEF-induced anti-inflammatory activity and ATX regulation.


Asunto(s)
Dermatitis Atópica/tratamiento farmacológico , Modelos Animales de Enfermedad , Hidrolasas Diéster Fosfóricas/sangre , Extractos Vegetales/uso terapéutico , Administración Oral , Animales , Estudios de Casos y Controles , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/metabolismo , Dinitrofluorobenceno/administración & dosificación , Masculino , Ratones , Extractos Vegetales/administración & dosificación
18.
J Affect Disord ; 215: 23-29, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28314177

RESUMEN

BACKGROUND: Panax ginseng Meyer extracts have been used to improve mood and alleviate symptoms of depression. However, little is known about the extracts' active ingredients and the molecular mechanisms underlying their reported anti-depressive effects. METHODS: Gintonin is an exogenous lysophosphatidic acid (LPA) receptor ligand isolated from P. ginseng. BON cells, an enterochromaffin cell line, and C57BL/6 mice were used to investigate whether gintonin stimulates serotonin release. Furthermore, the effects of gintonin on depressive-like behaviors following alcohol withdrawal were evaluated using the forced swim and tail suspension tests. RESULTS: Treatment of BON cells with gintonin induced a transient increase in the intracellular calcium concentration and serotonin release in a concentration- and time-dependent manner via the LPA receptor signaling pathway. Oral administration of the gintonin-enriched fraction (GEF) induced an increase in the plasma serotonin concentration in the mice. Oral administration of the GEF in mice with alcohol withdrawal decreased the immobility time in two depression-like behavioral tests and restored the alcohol withdrawal-induced serotonin decrease in plasma levels. LIMITATIONS: We cannot exclude the possibility that the gintonin-mediated regulation of adrenal catecholamine release in the peripheral system, and acetylcholine and glutamate release in the central nervous system, could also contribute to the alleviation of depressive-like behaviors. CONCLUSION: The GEF-mediated attenuation of depressive-like behavior induced by alcohol withdrawal may be mediated by serotonin release from intestinal enterochromaffin cells. Therefore, the GEF might be responsible for the ginseng extract-induced alleviation of depression-related symptoms.


Asunto(s)
Fitoterapia , Extractos Vegetales/uso terapéutico , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Acetilcolina/metabolismo , Animales , Calcio/metabolismo , Catecolaminas , Modelos Animales de Enfermedad , Ácido Glutámico/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Panax , Receptores del Ácido Lisofosfatídico/uso terapéutico
19.
J Vet Sci ; 18(3): 387-397, 2017 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-27586470

RESUMEN

Ginseng gintonin is an exogenous ligand of lysophosphatidic acid (LPA) receptors. Accumulating evidence shows LPA helps in rapid recovery of corneal damage. The aim of this study was to evaluate the therapeutic efficacy of gintonin in a rabbit model of corneal damage. We investigated the signal transduction pathway of gintonin in human corneal epithelium (HCE) cells to elucidate the underlying molecular mechanism. We next evaluated the therapeutic effects of gintonin, using a rabbit model of corneal damage, by undertaking histochemical analysis. Treatment of gintonin to HCE cells induced transient increases of [Ca2+]i in concentration-dependent and reversible manners. Gintonin-mediated mobilization of [Ca2+]i was attenuated by LPA1/3 receptor antagonist Ki16425, phospholipase C inhibitor U73122, inositol 1,4,5-triphosphate receptor antagonist 2-APB, and intracellular Ca2+ chelator BAPTA-AM. Gintonin facilitated in vitro wound healing in a concentration-dependent manner. When applied as an eye-drop to rabbits with corneal damage, gintonin rapidly promoted recovery. Histochemical analysis showed gintonin decreased corneal apoptosis and increased corneal cell proliferation. We demonstrated that LPA receptor activation by gintonin is linked to in vitro and in vivo therapeutic effects against corneal damage. Gintonin can be applied as a clinical agent for the rapid healing of corneal damage.


Asunto(s)
Lesiones de la Cornea/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Cicatrización de Heridas/efectos de los fármacos , Animales , Western Blotting/veterinaria , Calcio/metabolismo , Células Cultivadas , Córnea/efectos de los fármacos , Córnea/patología , Lesiones de la Cornea/patología , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Conejos , Receptores del Ácido Lisofosfatídico/efectos de los fármacos
20.
Neurochem Int ; 101: 56-65, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27765516

RESUMEN

We previously showed that gintonin, an exogenous lysophosphatidic acid (LPA) receptor ligand, attenuated ß-amyloid plaque formation in the cortex and hippocampus, and restored ß-amyloid-induced memory dysfunction. Both endogenous LPA and LPA receptors play a key role in embryonic brain development. However, little is known about whether gintonin can induce hippocampal cell proliferation in adult wild-type mice and an APPswe/PSEN-1 double Tg mouse model of Alzheimer's disease (AD). In the present study, we examined the effects of gintonin on the proliferation of hippocampal neural progenitor cells (NPCs) in vitro and its effects on the hippocampal cell proliferation in wild-type mice and a transgenic AD mouse model. Gintonin treatment increased 5-bromo-2'-deoxyuridine (BrdU) incorporation in hippocampal NPCs in a dose- and time-dependent manner. Gintonin (0.3 µg/ml) increased the immunostaining of glial fibrillary acidic protein, NeuN, and LPA1 receptor in hippocampal NPCs. However, the gintonin-induced increase in BrdU incorporation and immunostaining of biomarkers was blocked by an LPA1/3 receptor antagonist and Ca2+ chelator. Oral administration of the gintonin-enriched fraction (50 and 100 mg/kg) increased hippocampal BrdU incorporation and LPA1/3 receptor expression in adult wild-type and transgenic AD mice. The present study showed that gintonin could increase the number of hippocampal neurons in adult wild-type mice and a transgenic AD mouse model. Our results indicate that gintonin-mediated hippocampal cell proliferation contributes to the gintonin-mediated restorative effect against ß-amyloid-induced hippocampal dysfunction. These results support the use of gintonin for the prevention or treatment of neurodegenerative diseases such as AD via promotion of hippocampal neurogenesis.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Extractos Vegetales/farmacología , Enfermedad de Alzheimer/genética , Animales , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Neurogénesis/genética , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Extractos Vegetales/metabolismo , Presenilina-1/genética
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