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1.
Front Nutr ; 11: 1386389, 2024.
Article in English | MEDLINE | ID: mdl-39155930

ABSTRACT

Background: Kaempferol (KMP), a flavonoid in edible plants, exhibits diverse pharmacological effects. Growing body of evidence associates extended lifespan with physical activity (PA) and sleep, but KMP's impact on these behaviors is unclear. This double-blind, placebo-controlled, crossover trial assessed KMP's effects on PA and sleep. Methods: A total of 33 city workers (17 males and 16 females) participated in this study. They were randomly assigned to take either 10 mg of KMP or placebo for 2 weeks in the order allocated, with a 7-day washout period in between. All participants wore an accelerometer-based wearable device (Fitbit Charge 4), which monitored daily PA, heart rate (HR), and HR variability during sleep. Results: The duration of wearing the device was 23.73 ± 0.04 h/day. HR decreased in each PA level, and the mean daily step count and distance covered increased significantly during KMP intake compared to placebo. The outing rate, number of trips, number of recreational activities, and time spent in recreation on weekends increased. Sleep quality improved following KMP intake. The decrease in HR and increase in RMSSD may be important in mediating the effects of these KMPs. Conclusion: KMP leads to behavioral changes that subsequently improve sleep quality and potentially improve long-term quality of life. Clinical Trial Registration: https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000048447, UMIN000042438.

2.
Food Sci Nutr ; 11(9): 5427-5437, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37701215

ABSTRACT

Kaempferol (KMP) is an important flavonoid in many fruits and vegetables. Preclinical studies on KMP have reported its pharmacological effects, including antimicrobial, antioxidant, anti-inflammatory, antitumor, antidiabetic, myocardial protective, and neuroprotective effects. Additionally, some epidemiological studies have revealed a negative association between the consumption of KMP-containing foods and the risk of developing several disorders, such as cancer and cardiovascular diseases. Thus, although a large body of literature has demonstrated the benefits of KMP supplementation, there are no reports of clinical trials evaluating the safety of KMP aglycone administration or KMP aglycone-rich food consumption. The purpose of this study was to evaluate the safety of a high dose of KMP aglycone by administrating KMP aglycone-containing supplements to healthy adults. This study had a randomized, double-blind, placebo-controlled design and a 4-week duration. Participants were randomly allocated to the KMP (n = 24) or placebo (n = 24) group. For 4 weeks, the KMP group received a capsule containing 50-mg KMP daily, a dose approximately five times higher than the estimated human dietary intake. The placebo group received a capsule containing cornstarch-based powder daily. The general toxicity parameters were evaluated by examining the characteristics of the participants, hematological and blood biochemical parameters, general urinalysis, qualitative urine tests, and adverse events. No clinical changes were observed in anthropometric and blood pressure measurements or blood and urine parameters in the KMP group compared to those in the placebo group. Furthermore, no adverse events owing to KMP aglycone administration occurred. The study results revealed that the consumption of 50-mg KMP aglycone daily for 4 weeks is safe in healthy adults.

3.
J Nutr Biochem ; 103: 108949, 2022 05.
Article in English | MEDLINE | ID: mdl-35122998

ABSTRACT

Kaempferol (KMP) has numerous important biological functions, and we recently showed that it remarkably increased intracellular adenosine triphosphate (ATP) content in C2C12 myotubes under hypoxic conditions. Since intracellular ATP is generated by aerobic energy metabolism or anaerobic glycolysis, hypoxia inducible factor-1α (HIF-1α) has been shown to be associated with metabolic remodeling and causes metabolic shift from aerobic energy metabolism to anaerobic glycolysis in response to hypoxic conditions. Here, we investigate the effects of KMP under hypoxic conditions on the stabilization of HIF-1α in C2C12 myotubes and its underlying molecular mechanisms. Constitutive HIF-1α protein expression was observed in C2C12 myotubes, and its expression under hypoxic conditions was remarkably suppressed by KMP by reducing its stability; thus, resulting in an increase in ATP content. Furthermore, KMP strikingly increased the ubiquitination of HIF-1α and promoted its degradation via the ubiquitin proteasome system. Inhibition of HIF-1α by KMP resulted in the abrogation of the expression of glycolytic enzymes such as lactate dehydrogenase A and pyruvate dehydrogenase kinase isozyme 1. In addition, the metabolome profiling showed that KMP promoted oxidative energy production, while the mitochondrial complex activity assay indicated that KMP increased the activity of mitochondrial complex IV. Finally, we showed that KMP inhibited HIF-1α expression and increased intracellular ATP content in the soleus muscle of rats. Taken together, these results suggest that KMP increases intracellular ATP content under hypoxic conditions by suppressing the HIF-1α stabilization and/or by enhancing the mitochondrial complex IV activity in muscle.


Subject(s)
Adenosine Triphosphate , Mitochondria , Adenosine Triphosphate/metabolism , Animals , Hypoxia/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Kaempferols , Mitochondria/metabolism , Muscle Fibers, Skeletal/metabolism , Rats
4.
PLoS One ; 8(3): e58641, 2013.
Article in English | MEDLINE | ID: mdl-23536805

ABSTRACT

Accumulated evidence shows that some phytochemicals provide beneficial effects for human health. Recently, a number of mechanistic studies have revealed that direct interactions between phytochemicals and functional proteins play significant roles in exhibiting their bioactivities. However, their binding selectivities to biological molecules are considered to be lower due to their small and simple structures. In this study, we found that zerumbone, a bioactive sesquiterpene, binds to numerous proteins with little selectivity. Similar to heat-denatured proteins, zerumbone-modified proteins were recognized by heat shock protein 90, a constitutive molecular chaperone, leading to heat shock factor 1-dependent heat shock protein induction in hepa1c1c7 mouse hepatoma cells. Furthermore, oral administration of this phytochemical up-regulated heat shock protein expressions in the livers of Sprague-Dawley rats. Interestingly, pretreatment with zerumbone conferred a thermoresistant phenotype to hepa1c1c7 cells as well as to the nematode Caenorhabditis elegans. It is also important to note that several phytochemicals with higher hydrophobicity or electrophilicity, including phenethyl isothiocyanate and curcumin, markedly induced heat shock proteins, whereas most of the tested nutrients did not. These results suggest that non-specific protein modifications by xenobiotic phytochemicals cause mild proteostress, thereby inducing heat shock response and leading to potentiation of protein quality control systems. We considered these bioactivities to be xenohormesis, an adaptation mechanism against xenobiotic chemical stresses. Heat shock response by phytochemicals may be a fundamental mechanism underlying their various bioactivities.


Subject(s)
Heat-Shock Response/drug effects , Heat-Shock Response/physiology , Proteins/metabolism , Sesquiterpenes/pharmacology , Adaptation, Biological/drug effects , Adaptation, Biological/physiology , Animals , Cells, Cultured , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Female , Gene Expression Regulation/drug effects , HSP90 Heat-Shock Proteins/metabolism , Heat Shock Transcription Factors , Heat-Shock Proteins/chemistry , Heat-Shock Proteins/metabolism , Male , Mice , Phenotype , Protein Binding , Proteins/chemistry , Rats , Sesquiterpenes/metabolism , Temperature , Transcription Factors/genetics , Transcription Factors/metabolism
5.
Biochem Biophys Res Commun ; 382(2): 457-61, 2009 May 01.
Article in English | MEDLINE | ID: mdl-19289104

ABSTRACT

Intrinsic skin ageing is characterized by atrophy and loss of elasticity. Although the skin hypertrophy induced by photoageing has been studied, the molecular mechanisms of skin atrophy during ageing remain unclear. Here, we report that copper/zinc superoxide dismutase (CuZn-SOD)-deficient mice show atrophic morphology in their skin. This atrophy is accompanied by the degeneration of collagen and elastic fibers, and skin hydroxyproline is also significantly reduced in deficient mice. These imply that the dysfunction of collagen and elastin biosynthesis are involved in the progression of skin thinning. Furthermore, transdermal administration of a vitamin C derivative which can permeate through the membrane, completely reversed the skin thinning and deterioration of collagen and elastin in the mutant mice. These indicate that the vitamin C derivative is a powerful agent for alleviating skin ageing through regeneration of collagen and elastin. The CuZn-SOD-deficient mice might be applicable to evaluation of therapeutic medicines against skin ageing.


Subject(s)
Ascorbic Acid/analogs & derivatives , Skin Aging/drug effects , Skin/drug effects , Superoxide Dismutase/genetics , Animals , Ascorbic Acid/pharmacology , Ascorbic Acid/therapeutic use , Atrophy/drug therapy , Atrophy/genetics , Atrophy/pathology , Collagen/metabolism , Cytoplasm , Elastin/metabolism , Mice , Mice, Knockout , Skin/enzymology , Skin/pathology , Skin Aging/genetics , Superoxide Dismutase-1
6.
J Neurochem ; 107(6): 1730-40, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19014378

ABSTRACT

Parkinson's disease (PD) is a neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta. Although understanding of the pathogenesis of PD remains incomplete, increasing evidence from human and animal studies has suggested that oxidative stress is an important mediator in its pathogenesis. Astaxanthin (Asx), a potent antioxidant, has been thought to provide health benefits by decreasing the risk of oxidative stress-related diseases. This study examined the protective effects of Asx on 6-hydroxydopamine (6-OHDA)-induced apoptosis in the human neuroblastoma cell line SH-SY5Y. Pre-treatment of SH-SY5Y cells with Asx suppressed 6-OHDA-induced apoptosis in a dose-dependent manner. In addition, Asx strikingly inhibited 6-OHDA-induced mitochondrial dysfunctions, including lowered membrane potential and the cleavage of caspase 9, caspase 3, and poly(ADP-ribose) polymerase. In western blot analysis, 6-OHDA activated p38 MAPK, c-jun NH(2)-terminal kinase 1/2, and extracellular signal-regulated kinase 1/2, while Asx blocked the phosphorylation of p38 MAPK but not c-jun NH(2)-terminal kinase 1/2 and extracellular signal-regulated kinase 1/2. Pharmacological approaches showed that the activation of p38 MAPK has a critical role in 6-OHDA-induced mitochondrial dysfunctions and apoptosis. Furthermore, Asx markedly abolished 6-OHDA-induced reactive oxygen species generation, which resulted in the blockade of p38 MAPK activation and apoptosis induced by 6-OHDA treatment. Taken together, the present results indicated that the protective effects of Asx on apoptosis in SH-SY5Y cells may be, at least in part, attributable to the its potent antioxidative ability.


Subject(s)
Adrenergic Agents/pharmacology , Apoptosis/drug effects , Neuroprotective Agents/pharmacology , Oxidopamine/pharmacology , Annexin A5/metabolism , Caspase 3/metabolism , Cell Line, Tumor , Cytochromes c/metabolism , DNA Fragmentation/drug effects , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Enzyme-Linked Immunosorbent Assay/methods , Gene Expression Regulation, Neoplastic/drug effects , Humans , Membrane Potential, Mitochondrial/drug effects , Neuroblastoma/pathology , Reactive Oxygen Species/metabolism , Xanthophylls/pharmacology , p38 Mitogen-Activated Protein Kinases/metabolism
7.
Life Sci ; 83(1-2): 43-9, 2008 Jul 04.
Article in English | MEDLINE | ID: mdl-18538348

ABSTRACT

Interleukin (IL)-1beta is a proinflammatory cytokine responsible for the onset of a broad range of diseases, such as inflammatory bowel disease and rheumatoid arthritis. We have recently found that aggregated ursolic acid (UA), a triterpene carboxylic acid, is recognized by CD36 for generating reactive oxygen species (ROS) via NADPH oxidase (NOX) activation, thereby releasing IL-1beta protein from murine peritoneal macrophages (pMphi) in female ICR mice. In the present study, we investigated the ability of UA for inducing IL-1beta production in pMphi from 4 different strains of female mice (C57BL/6J, C3H/He, DDY, and ICR), as well as an established macrophage line (RAW264.7 cells). The levels of IL-1beta released from UA-treated pMphi of C57BL/6J and DDY mice were significantly lower than from those of ICR mice, whereas IL-1beta was not released from the pMphi of C3H/He mice or RAW264.7 cells. Of paramount importance, CD36 as well as the NOX components gp91phox and p47phox (C3H/He mice) and gp91phox (RAW264.7 cells) were scarcely detected. In addition, the different susceptibilities to UA-induced IL-1beta release were suggested to be correlated with the amount of superoxide anion (O2-) generated from the 5 different types of Mphi. Notably, intracellular, but not extracellular, O2- generation was indicated to play a major role in UA-induced IL-1beta release. Together, our results indicate that the UA-induced IL-1beta release was strain-dependent, and the expression status of CD36 and gp91phox is strongly associated with inducibility.


Subject(s)
Interleukin-1beta/metabolism , Macrophages/immunology , Triterpenes/pharmacology , Animals , Cell Line , Cells, Cultured , Female , Macrophages/drug effects , Macrophages/enzymology , Mice , Mice, Inbred ICR , Mice, Inbred Strains , NADPH Oxidases/genetics , NADPH Oxidases/metabolism , Onium Compounds/pharmacology , Protein Subunits/genetics , Protein Subunits/metabolism , RNA, Messenger/metabolism , Receptors, Scavenger/genetics , Receptors, Scavenger/metabolism , Species Specificity , Superoxide Dismutase/pharmacology , Superoxides/metabolism , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Ursolic Acid
8.
Mol Nutr Food Res ; 52(1): 26-42, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18203131

ABSTRACT

There is growing interest in the elucidation of the biological functions of triterpenoids, ubiquitously distributed throughout the plant kingdom, some of which are used as anticancer and anti-inflammatory agents in Asian countries. Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid, is the major component of some traditional medicine herbs and is well known to possess a wide range of biological functions, such as antioxidative, anti-inflammation, and anticancer activities, that are able to counteract endogenous and exogenous biological stimuli. In contrast to these beneficial properties, some laboratory studies have recently revealed that the effects of UA on normal cells and tissues are occasionally pro-inflammatory. Thus, UA may be designated as a double-edged sword with both positive and negative effects, and further evaluations of the effects of UA on the biological status of target cells or tissues are necessary. This review summarizes previous and current information regarding UA, and provides new insights into the underlying molecular mechanisms of its activities.


Subject(s)
Anti-Inflammatory Agents , Inflammation/chemically induced , Triterpenes , Animals , Anticarcinogenic Agents , Antimutagenic Agents , Apoptosis , Humans , Liver Diseases/prevention & control , Oxidative Stress , Plants, Medicinal/chemistry , Triterpenes/analysis , Triterpenes/metabolism , Triterpenes/therapeutic use , Ursolic Acid
9.
J Immunol ; 178(8): 4854-64, 2007 Apr 15.
Article in English | MEDLINE | ID: mdl-17404266

ABSTRACT

IL-1beta has been shown to play a pivotal role in the development of inflammatory disorders. We recently found that a natural triterpene, ursolic acid (UA), enhanced MIF release from nonstimulated macrophages. In this study, we examined the effects of UA on the production of several cytokines in resident murine peritoneal macrophages (pMphi). UA increased the protein release of IL-1beta, IL-6, and MIF, but not of TNF-alpha, in dose- and time-dependent manners. This triterpene also strikingly induced the activation of p38 MAPK and ERK1/2 together with that of upstream kinases. The release of UA-induced IL-1beta was significantly inhibited by the inhibitors of p38 MAPK, MEK1/2, ATP-binding cassette transporter, and caspase-1. Furthermore, UA induced intracellular ROS generation for IL-1beta production, which was suppressed by an antioxidant. Pretreatment with an anti-CD36 Ab significantly suppressed IL-1beta release, and surface plasmon resonance assay results showed that UA bound to CD36 on macrophages. In addition, the amount of IL-1beta released from UA-treated pMphi of CD36-deficient mice was markedly lower than that from those of wild-type mice. Interestingly, UA was found to aggregate in culture medium, and the aggregates were suggested to be responsible for IL-1beta production. In addition, i.p. administration of UA increased the levels of IL-1beta secretion and MPO activity in colonic mucosa of ICR mice. Taken together, our results indicate that aggregated UA is recognized, in part, by CD36 on macrophages for generating ROS, thereby activating p38 MAPK, ERK1/2, and caspase-1, as well as releasing IL-1beta protein via the ATP-binding cassette transporter.


Subject(s)
CD36 Antigens/physiology , Interleukin-1beta/biosynthesis , Macrophages, Peritoneal/drug effects , Triterpenes/pharmacology , Animals , Biosensing Techniques , Cells, Cultured , Extracellular Signal-Regulated MAP Kinases/physiology , Female , Interleukin-6/metabolism , Intramolecular Oxidoreductases/metabolism , MAP Kinase Signaling System/drug effects , Macrophage Migration-Inhibitory Factors/metabolism , Macrophages, Peritoneal/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Peroxidase/metabolism , Reactive Oxygen Species , p38 Mitogen-Activated Protein Kinases/physiology , Ursolic Acid
10.
Biosci Biotechnol Biochem ; 70(4): 1033-7, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16636478

ABSTRACT

An anti-inflammatory triterpenoid, ursolic acid (UA), has recently been found unexpectedly to induce the release of a pro-inflammatory mediator in resting macrophages. In this study, we found that topical applications of UA to mouse skin twice a week for 2 weeks significantly enhanced mRNA expression of cyclooxygenase (COX)-1, COX-2, and tumor necrosis factor-alpha, whereas its effect on tumor promotion was unclear.


Subject(s)
Cyclooxygenase 1/genetics , Cyclooxygenase 2/genetics , Gene Expression Regulation/drug effects , Skin/drug effects , Skin/metabolism , Triterpenes/pharmacology , Tumor Necrosis Factor-alpha/genetics , Animals , Carcinogenicity Tests , Inflammation Mediators/metabolism , Mice , Mice, Inbred ICR , Neoplasms/chemically induced , Neoplasms/pathology , RNA, Messenger/genetics , Tetradecanoylphorbol Acetate/pharmacology , Ursolic Acid
11.
Biochem Pharmacol ; 70(10): 1497-505, 2005 Nov 15.
Article in English | MEDLINE | ID: mdl-16188240

ABSTRACT

Macrophage migration inhibitory factor (MIF) plays some pivotal roles in innate immunity and inflammation. Ursolic acid (UA), an anti-inflammatory triterpene carboxylic acid, was recently reported to induce the release of pro-inflammatory mediators in resting macrophages (Mvarphi). We investigated the effects of UA on MIF protein release in resting RAW264.7 mouse Mvarphi, and found that it decreased intracellular MIF protein levels and promoted the release of MIF into the culture media in dose- and time-dependent manners, without affecting mRNA levels. Further, the triterpene strikingly induced activation of mitogen-activated protein kinase kinase 1/2 (MEK1/2) and extracellular signal-regulated kinase 1/2 (ERK1/2) within 30min, whereas no phosphorylation of p38 MAPK or JNK protein was observed. In addition, UA-promoted MIF release was significantly inhibited by PD98059, a MEK1/2 inhibitor, while siRNA for ERK2, but not ERK1, significantly decreased the amount of MIF protein released. These results suggest that UA triggers the release of intracellular MIF protein through the ERK2 activation.


Subject(s)
Macrophage Migration-Inhibitory Factors/metabolism , Macrophages/metabolism , Mitogen-Activated Protein Kinase 1/metabolism , Triterpenes/pharmacology , Animals , Blotting, Western/methods , Cell Line , Cell Membrane/drug effects , Cell Membrane/physiology , Cell Survival/drug effects , Cell Survival/physiology , Dose-Response Relationship, Drug , Gene Expression/drug effects , Gene Expression/genetics , MAP Kinase Kinase Kinase 1/drug effects , MAP Kinase Kinase Kinase 1/metabolism , Macrophages/drug effects , Mice , Mitogen-Activated Protein Kinase 1/drug effects , Mitogen-Activated Protein Kinase 3/drug effects , Mitogen-Activated Protein Kinase 3/metabolism , Phosphorylation , RNA, Messenger/genetics , RNA, Small Interfering/drug effects , RNA, Small Interfering/genetics , Reverse Transcriptase Polymerase Chain Reaction/methods , Time Factors , Ursolic Acid
12.
Asian Pac J Cancer Prev ; 6(4): 437-48, 2005.
Article in English | MEDLINE | ID: mdl-16435988

ABSTRACT

Okinawa prefecture in Japan is a distinct area characterized by unique traditional food habits and longevity. Prolonged exposure to activated leukocytes, playing pivotal roles in chronic inflammation-associated carcinogenesis, is known to lead to oxidative and nitrosative damage to macromolecules in the body since they are primary sources of free radicals, such as superoxide anion (O(2)(-)) and nitric oxide (NO). In this study, we estimated anti-oxidative and anti-nitrosative activities of Okinawan food items by employing two cellular experimental systems: (1) phorbol ester-induced O(2)(-) generation from differentiated HL-60 human promyelocytic leukemia cells; and (2) lipopolysaccharide (LPS)-induced NO generation in RAW264.7 murine macrophages. A total of 138 food items, consisting of 42 samples unique to Okinawa and 96 common in the Japanese main island, were purchased at local markets in Okinawa and extracted with chloroform. When tested at a concentration of 100 microg/ml, 38% (16/42) of the former showed 70% or more inhibition of O(2)(-) generation while 21% (20/96) of the latter did so. In parallel, 64% (27/42) of the former showed significant NO generation suppression in contrast to 48% (46/96) of the latter . Twenty-one active species were further tested at a concentration of 20 mug/ml, and eleven species, including sugar cane, wild turmeric, and zedoary, were indicated to be most promising items with anti-oxidative and anti-nitrosative properties. In addition, some of the active constituents (chebulagic acid, a resveratrol derivative, and sesquiterpenoids) were identified. Our results suggest that food items typical in the Okinawa area have higher cancer preventive potential than those common in Japan.


Subject(s)
Granulocyte Precursor Cells/drug effects , Macrophages/drug effects , Nitric Oxide/metabolism , Plants, Edible , Superoxides/metabolism , Animals , Cell Culture Techniques , Granulocyte Precursor Cells/metabolism , HL-60 Cells , Humans , Japan , Macrophages/metabolism , Mice , Plant Extracts/pharmacology , Plant Structures , Sesquiterpenes/pharmacology , Stilbenes/pharmacology
13.
Brain Res ; 982(2): 241-59, 2003 Aug 29.
Article in English | MEDLINE | ID: mdl-12915259

ABSTRACT

Taste bud cells (TBCs) on soft palates differ from those on tongues in innervation and chemosensitivity. We investigated voltage-gated channels involved in the taste responses of TBCs on mouse soft palates under in-situ tight-seal voltage/current-clamp conditions. Under the cell-attached mode, TBCs spontaneously fired action currents, which were blocked by application of 1 microM TTX to TBC basolateral membranes. Firing frequencies increased in response to taste substances applied to TBC receptor membranes. Under the whole-cell clamp mode, as expected, TBCs produced various voltage-gated currents such as TTX-sensitive Na+ currents (INa), outward currents (Iout) including TEA-sensitive and insensitive currents, inward rectifier K+ currents (Iir), and Ca2+ currents including T-type, P/Q-type, and L-type Ca2+ currents. We classified TBCs into three types based on the magnitude of their voltage-gated Na+ currents and membrane capacitance. HEX type (60% of TBCs examined) was significantly larger in Na+ current magnitude and smaller in membrane capacitance than LEX type (23%). NEX type (17%) had no Na+ currents. HEX type was equally distributed within single taste buds, while LEX type was centrally distributed, and NEX type was peripherally distributed. There were correlations between these electrophysiological cell types and morphological cell types determined by three-dimensional reconstruction. The present results show that soft palate taste buds contain TBCs with different electrophysiological properties, and suggest that their co-operation is required in taste transduction.


Subject(s)
Action Potentials/physiology , Ion Channels/physiology , Palate, Soft/physiology , Taste Buds/physiology , Taste/physiology , Action Potentials/drug effects , Animals , Dose-Response Relationship, Drug , In Vitro Techniques , Ion Channel Gating/drug effects , Ion Channel Gating/physiology , Mice , Palate, Soft/drug effects , Taste/drug effects , Taste Buds/drug effects , Tetrodotoxin/pharmacology
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