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1.
J Med Internet Res ; 22(5): e16443, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32348254

RESUMO

BACKGROUND: Continuous photoplethysmography (PPG) monitoring with a wearable device may aid the early detection of atrial fibrillation (AF). OBJECTIVE: We aimed to evaluate the diagnostic performance of a ring-type wearable device (CardioTracker, CART), which can detect AF using deep learning analysis of PPG signals. METHODS: Patients with persistent AF who underwent cardioversion were recruited prospectively. We recorded PPG signals at the finger with CART and a conventional pulse oximeter before and after cardioversion over a period of 15 min (each instrument). Cardiologists validated the PPG rhythms with simultaneous single-lead electrocardiography. The PPG data were transmitted to a smartphone wirelessly and analyzed with a deep learning algorithm. We also validated the deep learning algorithm in 20 healthy subjects with sinus rhythm (SR). RESULTS: In 100 study participants, CART generated a total of 13,038 30-s PPG samples (5850 for SR and 7188 for AF). Using the deep learning algorithm, the diagnostic accuracy, sensitivity, specificity, positive-predictive value, and negative-predictive value were 96.9%, 99.0%, 94.3%, 95.6%, and 98.7%, respectively. Although the diagnostic accuracy decreased with shorter sample lengths, the accuracy was maintained at 94.7% with 10-s measurements. For SR, the specificity decreased with higher variability of peak-to-peak intervals. However, for AF, CART maintained consistent sensitivity regardless of variability. Pulse rates had a lower impact on sensitivity than on specificity. The performance of CART was comparable to that of the conventional device when using a proper threshold. External validation showed that 94.99% (16,529/17,400) of the PPG samples from the control group were correctly identified with SR. CONCLUSIONS: A ring-type wearable device with deep learning analysis of PPG signals could accurately diagnose AF without relying on electrocardiography. With this device, continuous monitoring for AF may be promising in high-risk populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT04023188; https://clinicaltrials.gov/ct2/show/NCT04023188.


Assuntos
Fibrilação Atrial/diagnóstico , Aprendizado Profundo/normas , Fotopletismografia/métodos , Dispositivos Eletrônicos Vestíveis/normas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudo de Prova de Conceito , Estudos Prospectivos
2.
JMIR Mhealth Uhealth ; 7(6): e12770, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31199302

RESUMO

BACKGROUND: Wearable devices have evolved as screening tools for atrial fibrillation (AF). A photoplethysmographic (PPG) AF detection algorithm was developed and applied to a convenient smartphone-based device with good accuracy. However, patients with paroxysmal AF frequently exhibit premature atrial complexes (PACs), which result in poor unmanned AF detection, mainly because of rule-based or handcrafted machine learning techniques that are limited in terms of diagnostic accuracy and reliability. OBJECTIVE: This study aimed to develop deep learning (DL) classifiers using PPG data to detect AF from the sinus rhythm (SR) in the presence of PACs after successful cardioversion. METHODS: We examined 75 patients with AF who underwent successful elective direct-current cardioversion (DCC). Electrocardiogram and pulse oximetry data over a 15-min period were obtained before and after DCC and labeled as AF or SR. A 1-dimensional convolutional neural network (1D-CNN) and recurrent neural network (RNN) were chosen as the 2 DL architectures. The PAC indicator estimated the burden of PACs on the PPG dataset. We defined a metric called the confidence level (CL) of AF or SR diagnosis and compared the CLs of true and false diagnoses. We also compared the diagnostic performance of 1D-CNN and RNN with previously developed AF detectors (support vector machine with root-mean-square of successive difference of RR intervals and Shannon entropy, autocorrelation, and ensemble by combining 2 previous methods) using 10 5-fold cross-validation processes. RESULTS: Among the 14,298 training samples containing PPG data, 7157 samples were obtained during the post-DCC period. The PAC indicator estimated 29.79% (2132/7157) of post-DCC samples had PACs. The diagnostic accuracy of AF versus SR was 99.32% (70,925/71,410) versus 95.85% (68,602/71,570) in 1D-CNN and 98.27% (70,176/71,410) versus 96.04% (68,736/71,570) in RNN methods. The area under receiver operating characteristic curves of the 2 DL classifiers was 0.998 (95% CI 0.995-1.000) for 1D-CNN and 0.996 (95% CI 0.993-0.998) for RNN, which were significantly higher than other AF detectors (P<.001). If we assumed that the dataset could emulate a sufficient number of patients in training, both DL classifiers improved their diagnostic performances even further especially for the samples with a high burden of PACs. The average CLs for true versus false classification were 98.56% versus 78.75% for 1D-CNN and 98.37% versus 82.57% for RNN (P<.001 for all cases). CONCLUSIONS: New DL classifiers could detect AF using PPG monitoring signals with high diagnostic accuracy even with frequent PACs and could outperform previously developed AF detectors. Although diagnostic performance decreased as the burden of PACs increased, performance improved when samples from more patients were trained. Moreover, the reliability of the diagnosis could be indicated by the CL. Wearable devices sensing PPG signals with DL classifiers should be validated as tools to screen for AF.


Assuntos
Algoritmos , Fibrilação Atrial/diagnóstico , Aprendizado Profundo/tendências , Fotopletismografia/normas , Idoso , Fibrilação Atrial/fisiopatologia , Eletrocardiografia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fotopletismografia/instrumentação , Fotopletismografia/métodos , Estudos Prospectivos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Seul
3.
J Ginseng Res ; 43(2): 209-217, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30962735

RESUMO

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.

4.
J Ginseng Res ; 42(1): 35-41, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29348720

RESUMO

Background: Recently, we identified a novel ginseng-derived lysophosphatidic acid receptor ligand, called gintonin. We showed that gintonin induces [Ca2+]i transient-mediated morphological changes, proliferation, and migration in cells expressing lysophosphatidic acid receptors and that oral administration of gintonin exhibits anti-Alzheimer disease effects in model mice. However, little is known about the intestinal absorption of gintonin. The aim of this study was to investigate gintonin absorption using two model systems. Methods: Gintonin membrane permeation was examined using a parallel artificial membrane permeation assay, and gintonin absorption was evaluated in a mouse everted intestinal sac model. Results: The parallel artificial membrane permeation assay showed that gintonin could permeate an artificial membrane in a dose-dependent manner. In the everted sac model, gintonin absorption increased with incubation time (from 0 min to 60 min), followed by a decrease in absorption. Gintonin absorption into everted sacs was also dose dependent, with a nonlinear correlation between gintonin absorption and concentration at 0.1-3 mg/mL and saturation at 3-5 mg/mL. Gintonin absorption was inhibited by the Rho kinase inhibitor Y-27632 and the sodium-glucose transporter inhibitor phloridzin. Moreover, lipid extraction with methanol also attenuated gintonin absorption, suggesting the importance of the lipid portion of gintonin in absorption. This result shows that gintonin might be absorbed through passive diffusion, paracellular, and active transport pathways. Conclusion: The present study shows that gintonin could be absorbed in the intestine through transcellular and paracellular diffusion, and active transport. In addition, the lipid component of gintonin might play a key role in its intestinal absorption.

5.
Biol Pharm Bull ; 40(7): 1063-1070, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28674249

RESUMO

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.


Assuntos
Dermatite Atópica/tratamento farmacológico , Modelos Animais de Doenças , Diester Fosfórico Hidrolases/sangue , Extratos Vegetais/uso terapêutico , Administração Oral , Animais , Estudos de Casos e Controles , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/metabolismo , Dinitrofluorbenzeno/administração & dosagem , Masculino , Camundongos , Extratos Vegetais/administração & dosagem
6.
J Affect Disord ; 215: 23-29, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28314177

RESUMO

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.


Assuntos
Fitoterapia , Extratos Vegetais/uso terapêutico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Acetilcolina/metabolismo , Animais , Cálcio/metabolismo , Catecolaminas , Modelos Animais de Doenças , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Panax , Receptores de Ácidos Lisofosfatídicos/uso terapêutico
7.
J Vet Sci ; 18(3): 387-397, 2017 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-27586470

RESUMO

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.


Assuntos
Lesões da Córnea/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Cicatrização/efeitos dos fármacos , Animais , Western Blotting/veterinária , Cálcio/metabolismo , Células Cultivadas , Córnea/efeitos dos fármacos , Córnea/patologia , Lesões da Córnea/patologia , Relação Dose-Resposta a Droga , Humanos , Masculino , Coelhos , Receptores de Ácidos Lisofosfatídicos/efeitos dos fármacos
8.
Neurochem Int ; 101: 56-65, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27765516

RESUMO

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.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Extratos Vegetais/farmacologia , Doença de Alzheimer/genética , Animais , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Extratos Vegetais/metabolismo , Presenilina-1/genética
9.
J Ginseng Res ; 40(4): 325-333, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27746684

RESUMO

BACKGROUND: Ginseng extracts are known to have angiogenic effects. However, to date, only limited information is available on the molecular mechanism underlying the angiogenic effects and the main components of ginseng that exert these effects. Human umbilical-vein endothelial cells (HUVECs) are used as an in vitro model for screening therapeutic agents that promote angiogenesis and wound healing. We recently isolated gintonin, a novel ginseng-derived lysophosphatidic acid (LPA) receptor ligand, from ginseng. LPA plays a key role in angiogenesis and wound healing. METHODS: In the present study, we investigated the in vitro effects of gintonin on proliferation, migration, and tube formation of HUVECs, which express endogenous LPA1/3 receptors. RESULTS: Gintonin stimulated proliferation and migration of HUVECs. The LPA1/3 receptor antagonist, Ki16425, short interfering RNA against LPA1 or LPA3 receptor, and the Rho kinase inhibitor, Y-27632, significantly decreased the gintonin-induced proliferation, migration, and tube formation of HUVECs, which indicates the involvement of LPA receptors and Rho kinase activation. Further, gintonin increased the release of vascular endothelial growth factors from HUVECs. The cyclooxygenase-2 inhibitor NS-398, nuclear factor kappa B inhibitor BAY11-7085, and c-Jun N-terminal kinase inhibitor SP600125 blocked the gintonin-induced migration, which shows the involvement of cyclooxygenase-2, nuclear factor kappa B, and c-Jun N-terminal kinase signaling. CONCLUSION: The gintonin-mediated proliferation, migration, and vascular-endothelial-growth-factor release in HUVECs via LPA-receptor activation may be one of in vitro mechanisms underlying ginseng-induced angiogenic and wound-healing effects.

10.
Biomol Ther (Seoul) ; 24(4): 410-7, 2016 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-27098860

RESUMO

Quercetin is a flavonoid usually found in fruits and vegetables. Aside from its antioxidative effects, quercetin, like other flavonoids, has a various neuropharmacological actions. Quercetin-3-O-rhamnoside (Rham1), quercetin-3-O-rutinoside (Rutin), and quercetin- 3-(2(G)-rhamnosylrutinoside (Rham2) are mono-, di-, and tri-glycosylated forms of quercetin, respectively. In a previous study, we showed that quercetin can enhance α7 nicotinic acetylcholine receptor (α7 nAChR)-mediated ion currents. However, the role of the carbohydrates attached to quercetin in the regulation of α7 nAChR channel activity has not been determined. In the present study, we investigated the effects of quercetin glycosides on the acetylcholine induced peak inward current (IACh) in Xenopus oocytes expressing the α7 nAChR. IACh was measured with a two-electrode voltage clamp technique. In oocytes injected with α7 nAChR copy RNA, quercetin enhanced IACh, whereas quercetin glycosides inhibited IACh. Quercetin glycosides mediated an inhibition of IACh, which increased when they were pre-applied and the inhibitory effects were concentration dependent. The order of IACh inhibition by quercetin glycosides was Rutin≥Rham1>Rham2. Quercetin glycosides-mediated IACh enhancement was not affected by ACh concentration and appeared voltage-independent. Furthermore, quercetin-mediated IACh inhibition can be attenuated when quercetin is co-applied with Rham1 and Rutin, indicating that quercetin glycosides could interfere with quercetin-mediated α7 nAChR regulation and that the number of carbohydrates in the quercetin glycoside plays a key role in the interruption of quercetin action. These results show that quercetin and quercetin glycosides regulate the α7 nAChR in a differential manner.

11.
Biol Pharm Bull ; 39(2): 156-62, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26830477

RESUMO

Lysophosphatidic acid (1-acyl-2-lyso-sn-glycero-3-phosphatidic acid; LPA) is a simple and minor phospholipid in plants. Plant LPAs are merely metabolic intermediates in de novo lipid synthesis in plant cell membranes or for glycerophospholipid storage. The production and metabolisms of LPAs in animals are also well characterized and LPAs have diverse cellular effects in animal systems; i.e., from brain development to wound healing through the activation of G protein-coupled LPA receptors. Recent studies show that various foodstuffs such as soybean, cabbage and seeds such as sesame and sunflower contain bioactive LPAs. Some LPAs are produced from phosphatidic acid during the digestion of foodstuff. In addition, herbal medicines such as corydalis tuber, and especially ginseng, contain large amounts of LPAs compared to foodstuffs. Herbal LPAs bind to cell surface LPA receptors in animal cells and exert their biological effects. Herbal LPAs elicit [Ca(2+)]i transient and are coupled to various Ca(2+)-dependent ion channels and receptor regulations via the activation of LPA receptors. They also showed beneficial effects of in vitro wound healing, in vivo anti-gastric ulcer, anti-Alzheimer's disease, autotaxin inhibition and anti-metastasis activity. Thus, herbal LPAs can be useful agents for human health. Humans can utilize exogenous plant-derived LPAs for preventive or therapeutic purposes if plant-derived LPAs are developed as functional foods or natural medicine targeting LPA receptors. This brief review article introduces the known rich sources of herbal LPAs and herbal LPA binding protein, describes their biological effects, and further addresses possible clinical applications.


Assuntos
Lisofosfolipídeos/química , Lisofosfolipídeos/farmacologia , Plantas/metabolismo , Animais , Lisofosfolipídeos/metabolismo , Estrutura Molecular , Preparações de Plantas/química , Plantas/química
12.
Neurosci Lett ; 612: 256-260, 2016 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-26706688

RESUMO

Ginseng has a long history of use as a tonic for restoration of vigor. One example of ginseng-derived tonic effect is that it can improve physical stamina under conditions of stress. However, the active ingredient and the underlying molecular mechanism responsible for the ergogenic effect are unknown. Recent studies show that ginseng contains a novel ingredient, gintonin, which consists of a unique class of herbal-medicine lysophosphatidic acids (LPAs). Gintonin activates G protein-coupled LPA receptors to produce a transient [Ca(2+)]i signal, which is coupled to diverse intra- and inter-cellular signal transduction pathways that stimulate hormone or neurotransmitter release. However, relatively little is known about how gintonin-mediated cellular modulation is linked to physical endurance. In the present study, systemic administration of gintonin, but not ginsenosides, in fasted mice increased blood glucose concentrations in a dose-dependent manner. Gintonin treatment elevated blood glucose to a maximum level after 30min. This elevation in blood glucose level could be abrogated by the LPA1/3 receptor antagonist, Ki16425, or the ß-adrenergic receptor antagonist, propranolol. Furthermore, gintonin-dependent enhanced performance of fasted mice in rotarod test was likewise abrogated by Ki16425. Gintonin also elevated plasma epinephrine and norepinephrine concentrations. The present study shows that gintonin mediates catecholamine release through activation of the LPA receptor and that activation of the ß-adrenergic receptor is coupled to liver glycogenolysis, thereby increasing the supply of glucose and enhancing performance in the rotarod test. Thus, gintonin acts via the LPA-catecholamine-glycogenolysis axis, representing a candidate mechanism that can explain how ginseng treatment enhances physical stamina.


Assuntos
Catecolaminas/metabolismo , Atividade Motora/efeitos dos fármacos , Extratos Vegetais/farmacologia , Receptores de Ácidos Lisofosfatídicos/metabolismo , Glândulas Suprarrenais/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Animais , Glicemia/metabolismo , Epinefrina/sangue , Jejum , Glicogenólise , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Norepinefrina/sangue , Condicionamento Físico Animal , Resistência Física/efeitos dos fármacos , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Teste de Desempenho do Rota-Rod
13.
Front Pharmacol ; 6: 245, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26578955

RESUMO

Ginseng, the root of Panax ginseng, is used as a traditional medicine. Despite the long history of the use of ginseng, there is no specific scientific or clinical rationale for ginseng pharmacology besides its application as a general tonic. The ambiguous description of ginseng pharmacology might be due to the absence of a predominant active ingredient that represents ginseng pharmacology. Recent studies show that ginseng abundantly contains lysophosphatidic acids (LPAs), which are phospholipid-derived growth factor with diverse biological functions including those claimed to be exhibited by ginseng. LPAs in ginseng form a complex with ginseng proteins, which can bind and deliver LPA to its cognate receptors with a high affinity. As a first messenger, gintonin produces second messenger Ca(2+) via G protein-coupled LPA receptors. Ca(2+) is an intracellular mediator of gintonin and initiates a cascade of amplifications for further intercellular communications by activation of Ca(2+)-dependent kinases, receptors, gliotransmitter, and neurotransmitter release. Ginsenosides, which have been regarded as primary ingredients of ginseng, cannot elicit intracellular [Ca(2+)]i transients, since they lack specific cell surface receptor. However, ginsenosides exhibit non-specific ion channel and receptor regulations. This is the key characteristic that distinguishes gintonin from ginsenosides. Although the current discourse on ginseng pharmacology is focused on ginsenosides, gintonin can definitely provide a mode of action for ginseng pharmacology that ginsenosides cannot. This review article introduces a novel concept of ginseng ligand-LPA receptor interaction and proposes to establish a paradigm that shifts the focus from ginsenosides to gintonin as a major ingredient representing ginseng pharmacology.

14.
Biol Pharm Bull ; 38(10): 1631-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26424022

RESUMO

Gintonin is a novel ginseng-derived G protein-coupled lysophosphatidic acid (LPA) receptor ligand. Gintonin elicits an [Ca(2+)]i transient in animal cells via activation of LPA receptors. In vitro studies have shown that gintonin regulates various calcium-dependent ion channels and receptors. In in vivo studies, gintonin elicits anti-Alzheimer's disease activity through the activation of the non-amyloidogenic pathway and anti-metastatic effects through the inhibition of autotaxin. However, a method for gintonin quantitation in ginseng has not been developed. In the present study, we developed an enzyme immunoassay (EIA) to measure gintonin. A monoclonal antibody was raised in a mouse using gintonin as the immunogen, and an indirect competitive EIA was used to measure gintonin. The working range was 0.01-10 µg per assay. The anti-gintonin monoclonal antibody did not cross-react with the ginsenosides Ra, Rb1, Rb2, Rc, Rd, Re, Rf, Rg1, and Rg3 or with LPAs such as LPA C16:0, LPA C18:0, LPA C18:1, and LPA C18:2. Using a standard curve, we measured the amount of gintonin in various ginseng extract fractions. Interestingly, we only detected a little amount of gintonin in conventional hot water extracts of Korean red ginseng. However, we can measure gintonin after ethanol extraction of Korean red ginseng marc. Thus, gintonin can be extracted from ginseng with ethanol but not water, and the remaining Korean red ginseng marc can be used to obtain gintonin. These results indicate that the EIA with the anti-gintonin monoclonal antibody can be used to quantify gintonin in various ginseng preparations, including commercial ginseng products.


Assuntos
Anticorpos Monoclonais/imunologia , Técnicas Imunoenzimáticas , Extratos Vegetais/análise , Extratos Vegetais/imunologia , Animais , Linhagem Celular Tumoral , Etanol/química , Peroxidase do Rábano Silvestre , Camundongos Endogâmicos BALB C , Panax/química , Água/química
15.
Mol Cells ; 38(9): 796-805, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26255830

RESUMO

Gintonin is a novel ginseng-derived lysophosphatidic acid (LPA) receptor ligand. Oral administration of gintonin ameliorates learning and memory dysfunctions in Alzheimer's disease (AD) animal models. The brain cholinergic system plays a key role in cognitive functions. The brains of AD patients show a reduction in acetylcholine concentration caused by cholinergic system impairments. However, little is known about the role of LPA in the cholinergic system. In this study, we used gintonin to investigate the effect of LPA receptor activation on the cholinergic system in vitro and in vivo using wild-type and AD animal models. Gintonin induced [Ca(2+)]i transient in cultured mouse hippocampal neural progenitor cells (NPCs). Gintonin-mediated [Ca(2+)]i transients were linked to stimulation of acetylcholine release through LPA receptor activation. Oral administration of gintonin-enriched fraction (25, 50, or 100 mg/kg, 3 weeks) significantly attenuated scopolamine-induced memory impairment. Oral administration of gintonin (25 or 50 mg/kg, 2 weeks) also significantly attenuated amyloid-ß protein (Aß)-induced cholinergic dysfunctions, such as decreased acetylcholine concentration, decreased choline acetyltransferase (ChAT) activity and immunoreactivity, and increased acetylcholine esterase (AChE) activity. In a transgenic AD mouse model, long-term oral administration of gintonin (25 or 50 mg/kg, 3 months) also attenuated AD-related cholinergic impairments. In this study, we showed that activation of G protein-coupled LPA receptors by gintonin is coupled to the regulation of cholinergic functions. Furthermore, this study showed that gintonin could be a novel agent for the restoration of cholinergic system damages due to Aß and could be utilized for AD prevention or therapy.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Transtornos da Memória/tratamento farmacológico , Fragmentos de Peptídeos/metabolismo , Extratos Vegetais/administração & dosagem , Acetilcolina/metabolismo , Administração Oral , Doença de Alzheimer/metabolismo , Animais , Sinalização do Cálcio , Células Cultivadas , Colina O-Acetiltransferase/metabolismo , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/fisiologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Hipocampo/patologia , Masculino , Transtornos da Memória/induzido quimicamente , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/fisiologia , Escopolamina
16.
Neurosci Lett ; 603: 19-24, 2015 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-26191656

RESUMO

Lysophosphatidic acid (LPA) is a simple and minor phospholipid, but serves as a lipid-derived neurotransmitter via activation of G protein-coupled LPA receptors. Astrocytes abundantly express LPA receptors and contain gliotransmitters that modulate astrocyte-neuron interactions. Gintonin is a novel ginseng-derived G protein-coupled LPA receptor ligand. Gintonin induces [Ca(2+)]i transients in neuronal and non-neuronal cells via activation of LPA receptors, which regulate calcium-dependent ion channels and receptors. A line of evidence shows that neurotransmitter-mediated [Ca(2+)]i elevations in astrocytes are coupled with gliotransmitter release. However, little is known about whether gintonin-mediated [Ca(2+)]i transients are coupled to gliotransmitter release in astrocytes. In the present study, we examined the effects of gintonin on adenosine triphosphate (ATP) and glutamate release in mouse cortical primary astrocytes. Application of gintonin to astrocytes induced [Ca(2+)]i transients in a concentration-dependent and reversible manner. However, ginsenosides, other active ingredients in ginseng, had no effect on [Ca(2+)]i transients. The induction of gintonin-mediated [Ca(2+)]i transients was attenuated/blocked by the LPA1/3 receptor antagonist Ki16425, a phospholipase C inhibitor, an inositol 1,4,5-triphosphate receptor antagonist, and an intracellular Ca(2+) chelator. Gintonin treatment on astrocytes increased ATP and glutamate release in a concentration- and time-dependent manner. BAPTA and Ki16425 attenuated gintonin-mediated ATP and glutamate release in astrocytes. The present study shows that gintonin-mediated [Ca(2+)]i transients are coupled to gliotransmitter release via LPA receptor activation. Finally, gintonin-mediated [Ca(2+)]i transients and gliotransmitter release from astrocytes via LPA receptor activation might explain one mechanism of gintonin-mediated neuromodulation in the central nervous system.


Assuntos
Trifosfato de Adenosina/metabolismo , Astrócitos/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Lisofosfolipídeos/farmacologia , Panax/química , Animais , Astrócitos/metabolismo , Cálcio/metabolismo , Membrana Celular/metabolismo , Células Cultivadas , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Lisofosfolipídeos/isolamento & purificação , Camundongos , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais
17.
J Ginseng Res ; 39(3): 243-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26199556

RESUMO

BACKGROUND: Anticancer agents induce a variety of adverse effects when administered to cancer patients. Busulfan is a known antileukemia agent. When administered for treatment of leukemia in young patients, busulfan could cause damage to the male reproductive system as one of its adverse effects, resulting in sterility. METHODS: We investigated the effects of Korean Red Ginseng extract (KRGE) on busulfan-induced damage and/or dysfunction of the male reproductive system. RESULTS: We found that administration of busulfan to mice: decreased testis weight; caused testicular histological damage; reduced the total number of sperm, sperm motility, serum testosterone concentration; and eventually, litter size. Preadministration of KRGE partially attenuated various busulfan-induced damages to the male reproductive system. These results indicate that KRGE has a protective effect against busulfan-induced damage to the male reproduction system. CONCLUSION: The present study shows a possibility that KRGE could be applied as a useful agent to prevent or protect the male reproductive system from the adverse side effects induced by administration of anticancer agents such as busulfan.

18.
J Ginseng Res ; 39(4): 398-405, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26869834

RESUMO

BACKGROUND: Ginseng has been used as a tonic for invigoration of the human body. In a previous report, we identified a novel candidate responsible for the tonic role of ginseng, designated gintonin. Gintonin induces [Ca(2+)]i transient in animal cells via lysophosphatidic acid receptor activation. Gintonin-mediated [Ca(2+)]i transient is linked to anti-Alzheimer's activity in transgenic Alzheimer's disease animal model. The previous method for gintonin preparation included multiple steps. The aim of this study is to develop a simple method of gintonin fraction with a high yield. METHODS: We developed a brief method to obtain gintonin using ethanol and water. We extracted ginseng with fermentation ethanol and fractionated the extract with water to obtain water-soluble and water-insoluble fractions. The water-insoluble precipitate, rather than the water-soluble supernatant, induced a large [Ca(2+)]i transient in primary astrocytes. We designated this fraction as gintonin-enriched fraction (GEF). RESULTS: The yield of GEF was approximately 6-fold higher than that obtained in the previous gintonin preparation method. The apparent molecular weight of GEF, determined using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, was equivalent to that obtained in the previous gintonin preparation method. GEF induced [Ca(2+)]i transient in cortical astrocytes. The effective dose (ED50) was 0.3 ± 0.09 µg/mL. GEF used the same signal transduction pathway as gintonin during [Ca(2+)]i transient induction in mouse cortical astrocytes. CONCLUSION: Because GEF can be prepared through water precipitation of ginseng ethanol extract and is easily reproducible with high yield, it could be commercially utilized for the development of gintonin-derived functional health food and natural medicine.

19.
Arch Pharm Res ; 38(1): 108-14, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24895146

RESUMO

Quercetin, a representative flavonoid, is a compound of low molecular weight found in various colored plants and vegetables. Quercetin shows a wide range of neuropharmacological activities. In fact, quercetin naturally exists as monomer-(quercetin-3-O-rhamnoside) (Rham1), dimer-(Rutin), or trimer-glycosides [quercetin-3-(2(G)-rhamnosylrutinoside)] (Rham2) at carbon-3 in fruits and vegetables. The carbohydrate components are removed after ingestion into gastrointestinal systems. The role of the glycosides attached to quercetin in the regulation of γ-aminobutyric acid class C (GABAC) receptor channel activity has not been determined. In the present study, we examined the effects of quercetin glycosides on GABAC receptor channel activity by expressing human GABAC alone in Xenopus oocytes using a two-electrode voltage clamp technique and also compared the effects of quercetin glycosides with quercetin. We found that GABA-induced inward current (I GABA ) was inhibited by quercetin or quercetin glycosides. The inhibitory effects of quercetin and its glycosides on I GABA were concentration-dependent and reversible in the order of Rutin ≈ quercetin ≈ Rham 1 > Rham 2. The inhibitory effects of quercetin and its glycosides on I GABA were noncompetitive and membrane voltage-insensitive. These results indicate that quercetin and its glycosides regulate GABAC receptor channel activity through interaction with a different site from that of GABA, and that the number of carbohydrate attached to quercetin might play an important role in the regulation of GABAC receptor channel activity.


Assuntos
Antagonistas GABAérgicos/farmacologia , Glicosídeos/farmacologia , Quercetina/análogos & derivados , Receptores de GABA/fisiologia , Rutina/farmacologia , Animais , Humanos , Potenciais da Membrana/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Quercetina/farmacologia , Xenopus laevis
20.
Neurosci Lett ; 584: 356-61, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25445364

RESUMO

Gintonin is a novel ginseng-derived G protein-coupled lysophosphatidic acid (LPA) receptor ligand. Gintonin elicits an intracellular calcium concentration [Ca(2+)]i transient via activation of LPA receptors and regulates calcium-dependent ion channels and receptors. [Ca(2+)]i elevation by neurotransmitters or depolarization is usually coupled to neurotransmitter release in neuronal cells. Little is known about whether gintonin-mediated [Ca(2+)]i transients are also coupled to neurotransmitter release. The PC12 cell line is derived from a pheochromocytoma of the rat adrenal medulla and is widely used as a model for catecholamine release. In the present study, we examined the effects of gintonin on dopamine release in PC12 cells. Application of gintonin to PC12 cells induced [Ca(2+)]i transients in concentration-dependent and reversible manners. However, ginsenoside Rg3, another active ingredient of ginseng, induced a lagged and irreversible [Ca(2+)]i increase. The induction of gintonin-mediated [Ca(2+)]i transients was attenuated or blocked by the LPA1/3 receptor antagonist Ki16425, a phospholipase C inhibitor, an inositol 1,4,5-triphosphate receptor antagonist, and an intracellular Ca(2+) chelator. Repeated treatment with gintonin induced homologous desensitization of [Ca(2+)]i transients. Gintonin treatment in PC12 cells increased the release of dopamine in a concentration-dependent manner. Intraperitoneal administration of gintonin to mice also increased serum dopamine concentrations. The present study shows that gintonin-mediated [Ca(2+)]i transients are coupled to dopamine release via LPA receptor activation. Finally, gintonin-mediated [Ca(2+)]i transients and dopamine release via LPA receptor activation might explain one mechanism of gintonin-mediated inter-neuronal modulation in the nervous system.


Assuntos
Cálcio/metabolismo , Dopamina/metabolismo , Glicoproteínas/farmacologia , Panax/química , Receptores de Ácidos Lisofosfatídicos/metabolismo , Animais , Masculino , Camundongos Endogâmicos BALB C , Células PC12 , Ratos , Transdução de Sinais
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