RESUMO
Dysregulation of lipid metabolism and diabetes are risk factors for nonalcoholic fatty liver disease (NAFLD), and the gut-liver axis and intestinal microbiome are known to be highly associated with the pathogenesis of this disease. In Japan, the traditional medicine daisaikoto (DST) is prescribed for individuals affected by hepatic dysfunction. Herein, we evaluated the therapeutic potential of DST for treating NAFLD through modification of the liver and stool metabolome and microbiome by using STAM mice as a model of NAFLD. STAM mice were fed a high-fat diet with or without 3 % DST for 3 weeks. Plasma and liver of STAM, STAM with DST, and C57BL/6J ("Normal") mice were collected at 9 weeks, and stools at 4, 6, and 9 weeks of age. The liver pathology, metabolome and stool microbiome were analyzed. DST ameliorated the NAFLD activity score of STAM mice and decreased the levels of several liver lipid mediators such as arachidonic acid and its derivatives. In normal mice, nine kinds of family accounted for 94.1 % of microbiome composition; the total percentage of these family was significantly decreased in STAM mice (45.6 %), and DST administration improved this imbalance in microbiome composition (65.2 %). In stool samples, DST increased ursodeoxycholic acid content and altered several amino acids, which were correlated with changes in the gut microbiome and liver metabolites. In summary, DST ameliorates NAFLD by decreasing arachidonic acid metabolism in the liver; this amelioration seems to be associated with crosstalk among components of the liver, intestinal environment, and microbiome.
Assuntos
Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica , Aminoácidos/metabolismo , Animais , Ácidos Araquidônicos/metabolismo , Ácidos Araquidônicos/farmacologia , Ácidos Araquidônicos/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Microbioma Gastrointestinal/fisiologia , Japão , Lipídeos/farmacologia , Fígado/metabolismo , Medicina Tradicional , Metaboloma , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/patologia , Ácido Ursodesoxicólico/farmacologiaRESUMO
Kampo medicines are widely used in Japan; however, their potential to cause drug interactions still remains unclear and needs to be further investigated. The effects of goreisan on the P-glycoprotein (P-gp) and the cytochrome P-450 (CYP), which are associated with drug interactions, were investigated.The inhibitory effect of goreisan extract on P-gp was evaluated using a Caco-2 cell permeability assay. The results indicated that it inhibited P-gp function in a concentration-dependent manner.The inhibitory effect of three goreisan ingredients (alisol A, tumulosic acid, and (E)-cinnamic acid) on seven CYP isoforms was evaluated using human liver microsomes (HLM). Of these, tumulosic acid and (E)-cinnamic acid exhibited less than 16% inhibition at concentrations of 10 µmol/L against any of the CYP isoforms tested. Alisol A inhibited only CYP3A but showed no inhibitory effect with pre-incubation.These results indicate that goreisan extract has inhibitory activity against P-gp and that alisol A, a goreisan ingredient, exhibits an inhibitory effect on CYP3A. However, these are thought to be minor or negligible in vivo. Overall, these findings will be useful to evaluate possible drug interactions and provide support for the interpretation of future clinical drug-drug interaction studies involving goreisan.
Assuntos
Citocromo P-450 CYP3A , Medicamentos de Ervas Chinesas , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Células CACO-2 , Sistema Enzimático do Citocromo P-450 , Humanos , Microssomos HepáticosRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Ninjin'yoeito (NYT), a Japanese traditional Kampo medicine, has been reported to exert various clinical benefits such as relief from fatigue, malaise, anorexia, frailty, sarcopenia, and cognitive dysfunction. Recently, some review articles described the pharmacological effects of NYT and additionally indicated the possibility that multiple ingredients in NYT contribute to these effects. However, pharmacokinetic data on the ingredients are essential in addition to data on their pharmacological activities to accurately determine the active ingredients in NYT. AIM OF THE STUDY: This study assessed the in vivo pharmacokinetics of NYT using mice. MATERIALS AND METHODS: Target liquid chromatography-mass spectrometry (LC-MS) and wide target LC-MS or LC-tandem MS of NYT ingredients in plasma and the brain after oral administration of NYT were performed. Imaging MS was performed to investigate the detailed brain distributions of NYT ingredients. RESULTS: The concentrations of 13 ingredients in plasma and schizandrin in the brain were quantified via target LC-MS, and the wide target analysis illustrated that several ingredients are absorbed into blood and transported into the brain. Imaging MS revealed that schizandrin was homogenously dispersed in the NYT-treated mouse brain. CONCLUSION: These results should be useful for clarifying the active ingredients of NYT and their mechanisms of actions.
Assuntos
Encéfalo/metabolismo , Ciclo-Octanos/farmacocinética , Medicamentos de Ervas Chinesas/farmacocinética , Lignanas/farmacocinética , Compostos Policíclicos/farmacocinética , Administração Oral , Animais , Cromatografia Líquida , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Masculino , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Distribuição TecidualRESUMO
Maoto, a traditional kampo medicine, has been clinically prescribed for influenza infection and is reported to relieve symptoms and tissue damage. In this study, we evaluated the effects of maoto as an herbal multi-compound medicine on host responses in a mouse model of influenza infection. On the fifth day of oral administration to mice intranasally infected with influenza virus [A/PR/8/34 (H1N1)], maoto significantly improved survival rate, decreased viral titer, and ameliorated the infection-induced phenotype as compared with control mice. Analysis of the lung and plasma transcriptome and lipid mediator metabolite profile showed that maoto altered the profile of lipid mediators derived from ω-6 and ω-3 fatty acids to restore a normal state, and significantly up-regulated the expression of macrophage- and T-cell-related genes. Collectively, these results suggest that maoto regulates the host's inflammatory response by altering the lipid mediator profile and thereby ameliorating the symptoms of influenza.
Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Mediadores da Inflamação/metabolismo , Vírus da Influenza A , Influenza Humana/tratamento farmacológico , Influenza Humana/etiologia , Influenza Humana/metabolismo , Preparações de Plantas/administração & dosagem , Transcriptoma/efeitos dos fármacos , Animais , Antivirais , Modelos Animais de Doenças , Ephedra sinica , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/etiologia , Avaliação de Sintomas , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Carga Viral/efeitos dos fármacosRESUMO
In modern medical care in which Kampo and Western drugs are often combined, it is extremely important to clarify drug-drug interaction (DDI) to ensure safety and efficacy. However, there is little evidence of DDI in Kampo medicines. Therefore, as part of our studies to clarify the DDI risk for Kampo medicines, we evaluated the effects of five Kampo medicines [yokukansan (YKS), rikkunshito (RKT), shakuyakukanzoto (SKT), hangeshashinto (HST), and goshajinkigan (GJG)] that are widely used in Japan, on drug transporter P-glycoprotein (P-gp) using a Caco-2 permeability assay. These Kampo medicines inhibited the P-gp transport of digoxin through a Caco-2 cell monolayer. The IC50 values were 1.94-10.80 mg/ml. Of the five Kampo medicines, YKS showed the strongest inhibition (IC50 = 1.94 mg/ml), which was attributed to Uncariae Uncis Cum Ramulus. Unfortunately, we could not find the active ingredients responsible for its action. Finally, the Igut/IC50 values for the five Kampo medicines were calculated, and the DDI risk was objectively evaluated according to the criteria in the DDI guidance issued by the Japanese Ministry of Health, Labor, and Welfare and the US Food and Drug Administration. The Igut/IC50 values for the five Kampo medicines were ≤3.4. As these values were <10, they were evaluated as having a weak P-gp inhibitory effect that does not require further verification in humans, suggesting that the DDI risk due to P-gp inhibition for these Kampo medicines is low. The results should provide useful clinical information on the safety and efficacy of the combined use of Kampo and Western medicines.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Células CACO-2/metabolismo , Medicina Kampo/métodos , Interações Medicamentosas , Humanos , PermeabilidadeRESUMO
Many pharmaceutical agents not only require microbial metabolism for increased bioavailability and bioactivity, but also have direct effects on gut microbial assemblage and function. We examined the possibility that these actions are not mutually exclusive and may be mutually reinforcing in ways that enhance long-term of these agents. Daikenchuto, TU-100, is a traditional Japanese medicine containing ginseng. Conversion of the ginsenoside Rb1 (Rb1) to bioactive compound K (CK) requires bacterial metabolism. Diet-incorporated TU-100 was administered to mice over a period of several weeks. T-RFLP and 454 pyrosequencing were performed to analyze the time-dependent effects on fecal microbial membership. Fecal microbial capacity to metabolize Rb1 to CK was measured by adding TU-100 or ginseng to stool samples to assess the generation of bioactive metabolites. Levels of metabolized TU-100 components in plasma and in stool samples were measured by LC-MS/MS. Cecal and stool short-chain fatty acids were measured by GC-MS. Dietary administration of TU-100 for 28 days altered the gut microbiota, increasing several bacteria genera including members of Clostridia and Lactococcus lactis. Progressive capacity of microbiota to convert Rb1 to CK was observed over the 28 days administration of dietary TU-100. Concomitantly with these changes, increases in all SCFA were observed in cecal contents and in acetate and butyrate content of the stool. Chronic consumption of dietary TU-100 promotes changes in gut microbiota enhancing metabolic capacity of TU-100 and increased bioavailability. We believe these findings have broad implications in optimizing the efficacy of natural compounds that depend on microbial bioconversion in general.
RESUMO
A pharmaceutical grade Japanese traditional medicine, daikenchuto (TU-100), consisting of Japanese pepper, processed ginger, and ginseng, has been widely used for various intestinal disorders in Japan and now under development as a new therapeutic drug in the US. It is suggested that TU-100 ingredients exert pharmacological effects on intestines via two routes, from the luminal side before absorption and the peripheral blood stream after absorption. Therefore, in order to fully understand the pharmacological actions of TU-100, it is critically important to know the intraluminal amounts and forms of ingested TU-100 ingredients. In the present study, after administrating TU-100 to rats, the concentrations of TU-100 ingredients and their conjugates in the peripheral and portal blood and ileal contents were determined by LC-MS/MS. Next, TU-100 was administered to patients with ileostomy bags, but whose small intestines are diagnosed as healthy, and the ingredients/conjugates in the ileal effluent were analyzed. The results suggest that: (1) Pepper ingredients hydroxysanshools are rapidly absorbed and enter systemic circulation, (2) Ginseng ingredients ginsenosides are transported to the colon with the least absorption, (3) Ginger ingredients gingerols are absorbed and some conjugated in the small intestine and transported via the portal vein. While only a small amount of gingerols/gingerol conjugates enter systemic circulation, considerable amounts reappear in the small intestine. Thus, the effect of TU-100 on the intestines is believed to be a composite of multiple actions by multiple compounds supplied via multiple routes.
RESUMO
Shakuyakukanzoto (SKT) is a kampo medicine composed of equal proportions of Glycyrrhizae radix (G. radix) and Paeoniae radix (P. radix). A double-blind study reported that SKT significantly ameliorated painful muscle cramp in cirrhosis patients without the typical severe side effects of muscle weakness and central nervous system (CNS) depression. Previous basic studies reported that SKT and its active components induced relaxation by a direct action on skeletal muscle and that SKT did not depress CNS functions; however, why SKT has a lower incidence of muscle weakness remains unknown. In the present study, we investigated which components are absorbed into the blood of rats after a single oral administration of SKT to identify the active components of SKT. We also investigated the effects of SKT and its components on the twitch contraction induced by physiological Ca(2+) release. Our study demonstrated that SKT and five G. radix isolates, which are responsible for the antispasmodic effect of SKT, did not inhibit the twitch contraction in contrast to dantrolene sodium, a direct-acting peripheral muscle relaxant, indicating that the mechanisms of muscle contraction of SKT and dantrolene in skeletal muscle differ. These findings suggest that SKT does not reduce the contractile force in skeletal muscle under physiological conditions, i.e., SKT may have a low risk of causing muscle weakness in clinical use. Considering that most muscle relaxants and anticonvulsants cause various harmful side effects such as weakness and CNS depression, SKT appears to have a benign safety profile.