Genipin, a metabolite derived from the herbal medicine Inchin-ko-to, and suppression of Fas-induced lethal liver apoptosis in mice

Yamamoto, Masahiro; Miura, Noriaki; Ohtake, Nobuhiro; Amagaya, Sakae; Ishige, Atsushi; Sasaki, Hiroshi; Komatsu, Yasuhiro; Fukuda, Kazunori; Ito, Takashi; Terasawa, Katsutoshi

doi:10.1016/s0016-5085(00)70220-4

Cited by 122 publications

(104 citation statements)

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“…15) These observations suggest the possible mechanism of the protective effect of genipin against Ab25-35-induced cytotoxicity. These results all indicate that genipin and its congeners are potential candidates for the lead compound for treatment of Alzheimer's disease, and that they are unique in their ready accessibility to cellular target(s) across cell membranes (cf.…”

mentioning

confidence: 84%

Prevention of the Neurotoxicity of the Amyloid .BETA. Protein by Genipin.

Yamazaki

Sakura

Chiba

et al. 2001

Biological & Pharmaceutical Bulletin

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It is now generally documented that the cause of Alzheimer's disease is progressive deposition (histopathologically identified as senile plaque) of the amyloid b protein (Ab) (Ab1-42 and Ab1-40) with aging or due to genetic background in vulnerable brain regions, including the hippocampus and cortex. This deposition is strongly suspected to contribute to disruption of the neuronal network as a result of ubiquitous apoptotic cell death induced by Ab.1,2) The addition of Ab and its hydrophobic core fragments such as Ab25-35 (a monodecapeptide with an amino acid sequence identical to that from 25 to 35 of Ab) has been reported to induce significant cell death in approximately one week in primary cultures of rat hippocampal neurons. [3][4][5] Geniposide and genipin, iridoid compounds found in many plants such as Gardenia jasminoides, have been demonstrated in our laboratory to have neurotrophic, nerve growth factor (NGF)-like activity in their neuritogenesis and signaling promotion in PC12h cells, with genipin having the stronger effect.6,7) Administration of genipin counteracted the trauma-and scopolamine-induced impairment of memory in mice. 8) In some reported experiments, NGF and other neurotrophic factors reversed the deficit in spatial learning and memory in aged rats.9,10) We investigated whether these two iridoids can affect the neuronal toxicity of Ab in cultured hippocampal neurons.Hippocampal neurons from 18-d rat embryos were prepared as described previously.11) Hippocampal cells were maintained for 2 d in 48-well culture plates with Dulbecco's modified Eagle medium (DMEM) supplemented with 10% precolostrum new-born calf serum, selected for neuronal populations by incubation with cytosine-b-D-arabinofuranoside 10 mM for 24 h in Ca 2ϩ , Mg 2ϩ -free phosphate-buffered saline, pH 7.4 (CMF-PBS), and then treated with Ab25-35 (40 mM) in CMF-PBS for 2 d without serum. Ab25-35 was prepared using a peptide synthesizer according to the method described previously.11) It was dissolved in CMF-PBS at a concentration of 1.8 mM (most of the Ab was in fine suspension).Toxic effect on the cultures was evaluated by estimation of lactate dehydrogenase (LDH) release during 2 d of culture in the presence of Ab25-35 with and without test compounds as specified below and according to the method described previously. 12)Geniposide was kindly provided by Toyo F.C.C. Co. (Tokyo, Japan) and genipin was purchased from Wako Pure Chemical Industries (Osaka, Japan). They were dissolved in distilled water and refrigerated until use.The addition of Ab25-35 40 mM to the hippocampal neuron cultures markedly increased LDH release (Fig. 1, Ab25-35 only). Our colleagues previously found in cultured hippocampal cells that Ab25-35-induced plasma membrane impairment was blocked by the addition of the endonuclease inhibitor aurintricarboxylic acid, indicating that the cell degeneration was a result of apoptotic cell death.13) The neurotoxicity of Ab was effectively attenuated by the addition of genipin (20 mM or more) to the medium (Fig. 1A). ...

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confidence: 84%

Prevention of the Neurotoxicity of the Amyloid .BETA. Protein by Genipin.

Yamazaki

Sakura

Chiba

et al. 2001

Biological & Pharmaceutical Bulletin

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“…Chinese/Japanese herbal medicines are now manufactured under modern scientific quality controls in Japan and have been ethically administered to a wide range of patients for ϳ30 yr. Inchinkoto (ICKT), one such medicine, has been recognized as a "magic bullet" for jaundice and has long been used in Japan and China as a choleretic (1) and hepatoprotective (57,58) agent for various types of liver diseases. Genipin, an intestinal bacterial metabolite of geniposide, a major ingredient of Gardenia fructus in ICKT (2), enhances Mrp2-mediated choleretic activity, and modulates GSH contents in the liver (1,43,47).…”

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confidence: 99%

Inchinkoto, a herbal medicine, and its ingredients dually exert Mrp2/MRP2-mediated choleresis and Nrf2-mediated antioxidative action in rat livers

Okada

Shoda

Kano

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Inchinkoto, a herbal medicine, and its ingredients dually exert Mrp2/MRP2-mediated choleresis and Nrf2-mediated antioxidative action in rat livers. Am J Physiol Gastrointest Liver Physiol 292: G1450 -G1463, 2007. First published October 12, 2006; doi:10.1152/ajpgi.00302.2006, a herbal medicine, has been recognized in Japan and China as a "magic bullet" for jaundice. To explore potent therapeutic agents for cholestasis, the effects of ICKT or its ingredients on multidrug resistance-associated protein 2 (Mrp2/ MRP2)-mediated choleretic activity, as well as on antioxidative action, were investigated using rats and chimeric mice with livers that were almost completely repopulated with human hepatocytes. Biliary excretion of Mrp2 substrates and the protein mass, subcellular localization, and mRNA level of Mrp2 were assessed in rats after 1-wk oral administration of ICKT or genipin, a major ingredient of ICKT. Administration of ICKT or genipin to rats for 7 days increased bile flow and biliary excretion of bilirubin conjugates. Mrp2 protein and mRNA levels and Mrp2 membrane densities in the bile canaliculi and renal proximal tubules were significantly increased in ICKT-or genipin-treated rat livers and kidneys. ICKT and genipin, thereby, accelerated the disposal of intravenously infused bilirubin. The treatment also increased hepatic levels of heme oxygenase-1 and GSH by a nuclear factor-E2-related factor (Nrf2)-dependent mechanism. Similar effects of ICKT on MRP2 expression levels were observed in humanized livers of chimeric mice. In conclusion, these findings provide the rationale for therapeutic options of ICKT and its ingredients that should potentiate bilirubin disposal in vivo by enhancing Mrp2/MRP2-mediated secretory capacities in both livers and kidneys as well as Nrf2-mediated antioxidative actions in the treatment of cholestatic liver diseases associated with jaundice.

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“…In our test, the purgation effect of rheum (Yamamoto et al, 2000) possibly led to a decrease in the level of bilirubin. The level of bilirubin decreased significantly in the control-medication and medication groups, which corroborated the data from related reports on the purgation effect.…”

Section: Effect On Metabolism Of Digestion and Excretionmentioning

confidence: 52%

Metabolic analysis of the effect of rheum on a taurocholate-induced acute pancreatitis rat model

Chen

Shen

Yang

et al. 2017

Braz. J. Pharm. Sci.

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The effects of rheum on serum parameters in a taurocholate-induced acute pancreatitis (AP) rat model were investigated using pathological and biochemical tests, and a proton nuclear magnetic resonance ( 1 H NMR)-based metabonomic strategy. Healthy rats and rats with AP were either treated with rheum (7.5% at a dose of 1.5 g/kg) or left untreated. Serum samples were collected from the AP and rheum-treated groups at 6, 12, and 24 h after treatment. The effect of rheum on pathological changes in the pancreatic was investigated to validate the AP model. We obtained 1 H NMR spectra and analyzed the results using the partial least squares discriminant method. The results of the pathological and metabolic analyses revealed an amelioration of multiple metabolic abnormalities and an increase in the aerobic respiration ratio after treatment, compared with the AP groups. These results were attributed to improvements in energy supply and the elimination of metabolic products. The study also promoted NMR-based metabonomic analysis as a feasible method of assessing traditional Chinese drugs.

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Genipin, a metabolite derived from the herbal medicine Inchin-ko-to, and suppression of Fas-induced lethal liver apoptosis in mice

Cited by 122 publications

References 40 publications

Prevention of the Neurotoxicity of the Amyloid .BETA. Protein by Genipin.

Prevention of the Neurotoxicity of the Amyloid .BETA. Protein by Genipin.

Inchinkoto, a herbal medicine, and its ingredients dually exert Mrp2/MRP2-mediated choleresis and Nrf2-mediated antioxidative action in rat livers

Metabolic analysis of the effect of rheum on a taurocholate-induced acute pancreatitis rat model

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