Cytokines and their soluble receptors in human liver regeneration ?in vivo? and ?in vitro?

The recovery of approximately 40% of the total liver protein during the first day after partial hepatectomy was shown to be due to the near cessation of protein breakdown rather than to an increase in protein synthesis. The decrease in degradation of total protein was less if rats were adrenalectomized or protein-depleted prior to partial hepatectomy. The effect of these treatments originally suggested that changes in free amino acid levels in liver might be related to the rate of protein degradation. However, no correlation was found between levels of total free amino acids and rates of breakdown. Measurements of individual amino acids during liver regeneration suggested that levels of free methionine and phenylalanine, amino acids that have been found to lower rates of protein degradation in vitro, are not correlated with rates of breakdown in vivo. The difference between the fractional rate of ornithine aminotransferase degradation (0.68/day and 0.28/day in sham-hepatectomized and partially hepatectomized rats, respectively) was sufficient to account for the higher level of this protein 3 days after surgery in the latter group.

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In vitro inhibitory effect of obtusofolin on the activity of CYP3A4, 2C9, and 2E1

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03397-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Na Liu ◽

Ping Chen ◽

Xiaojun Du ◽

Junxia Sun ◽

Shasha Han

Keyword(s):

Human Liver ◽

Competitive Inhibition ◽

Liver Microsomes ◽

Inhibitory Effect ◽

Dependent Manner ◽

Cytochrome P450 Enzymes ◽

Inhibition Model ◽

Dose Dependent

Abstract Background Obtusofolin is the major active ingredient of Catsia tora L., which possesses the activity of improving eyesight and protecting the optic nerve. Investigation on the interaction of obtusofolin with cytochrome P450 enzymes (CYP450s) could provide a reference for the clinical application of obtusofolin. Methods The effect of obtusofolin on the activity of CYP450s was investigated in the presence of 100 μM obtusofolin in pooled human liver microsomes (HLMs) and fitted with the Lineweaver–Burk plots to characterize the specific inhibition model and kinetic parameters. Results Obtusofolin was found to significantly inhibited the activity of CYP3A4, 2C9, and 2E1. In the presence of 0, 2.5, 5, 10, 25, 50, and 100 μM obtusofolin, the inhibition of these CYP450s showed a dose-dependent manner with the IC50 values of 17.1 ± 0.25, 10.8 ± 0.13, and 15.5 ± 0.16 μM, respectively. The inhibition of CYP3A4 was best fitted with the non-competitive inhibition model with the Ki value of 8.82 μM. While the inhibition of CYP2C9 and 2E1 was competitive with the Ki values of 5.54 and 7.79 μM, respectively. After incubating for 0, 5, 10, 15, and 30 min, the inhibition of CYP3A4 was revealed to be time-dependent with the KI value of 4.87 μM− 1 and the Kinact value of 0.0515 min− 1. Conclusions The in vitro inhibitory effect of obtusofolin implying the potential drug-drug interaction between obtusofolin and corresponding substrates, which needs further in vivo validations.

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THIOPENTAL METABOLISM BY HUMAN LIVER IN VIVO AND IN VITRO

Survey of Anesthesiology ◽

10.1097/00132586-196704000-00016 ◽

1967 ◽

Vol 11 (2) ◽

pp. 112???113

Author(s):

L. C. MARK ◽

L. BRAND ◽

S. KAMVYSSI ◽

R. C. BRITTON ◽

J. M. PEREL ◽

...

Keyword(s):

Human Liver

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Augmenter of Liver Regeneration (ALR) Is a Novel Biomarker of Hepatocellular Stress/Inflammation: In Vitro, In Vivo and In Silico Studies

Molecular Medicine ◽

10.2119/molmed.2012.00183 ◽

2012 ◽

Vol 18 (11) ◽

pp. 1421-1429 ◽

Cited By ~ 15

Author(s):

Yoram Vodovotz ◽

John Prelich ◽

Claudio Lagoa ◽

Derek Barclay ◽

Ruben Zamora ◽

...

Keyword(s):

Liver Regeneration ◽

In Silico ◽

Augmenter Of Liver Regeneration ◽

In Silico Studies

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Effect of a New Prokinetic Agent DA-9701 Formulated with Corydalis Tuber and Pharbitidis Semen on Cytochrome P450 and UDP-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/650718 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 6

Author(s):

Hye Young Ji ◽

Kwang Hyeon Liu ◽

Ji Hyeon Jeong ◽

Dae-Young Lee ◽

Hyun Joo Shim ◽

...

Keyword(s):

Cytochrome P450 ◽

Human Liver ◽

Liver Microsomes ◽

Human Liver Microsomes ◽

Udp Glucuronosyltransferase ◽

Index Value ◽

Tuber Extract ◽

Corydalis Tuber

DA-9701 is a new botanical drug composed of the extracts of Corydalis tuber and Pharbitidis semen, and it is used as an oral therapy for the treatment of functional dyspepsia in Korea. The inhibitory potentials of DA-9701 and its component herbs, Corydalis tuber and Pharbitidis semen, on the activities of seven major human cytochrome P450 (CYP) enzymes and four UDP-glucuronosyltransferase (UGT) enzymes in human liver microsomes were investigated using liquid chromatography-tandem mass spectrometry. DA-9701 and Corydalis tuber extract slightly inhibited UGT1A1-mediated etoposide glucuronidation, with 50% inhibitory concentration (IC50) values of 188 and 290 μg/mL, respectively. DA-9701 inhibited CYP2D6-catalyzed bufuralol1′-hydroxylation with an inhibition constant (Ki) value of 6.3 μg/mL in a noncompetitive manner. Corydalis tuber extract competitively inhibited CYP2D6-mediated bufuralol1′-hydroxylation, with aKivalue of 3.7 μg/mL, whereas Pharbitidis semen extract showed no inhibition. The volume in which the dose could be diluted to generate an IC50equivalent concentration (volume per dose index) value of DA-9701 for inhibition of CYP2D6 activity was 1.16 L/dose, indicating that DA-9701 may not be a potent CYP2D6 inhibitor. Further clinical studies are warranted to evaluate thein vivoextent of the observedin vitrointeractions.

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The “Albumin Effect” and in Vitro-in Vivo Extrapolation: Sequestration of Long-Chain Unsaturated Fatty Acids Enhances Phenytoin Hydroxylation by Human Liver Microsomal and Recombinant Cytochrome P450 2C9

Drug Metabolism and Disposition ◽

10.1124/dmd.107.019885 ◽

2008 ◽

Vol 36 (5) ◽

pp. 870-877 ◽

Cited By ~ 57

Author(s):

Andrew Rowland ◽

David J. Elliot ◽

Kathleen M. Knights ◽

Peter I. Mackenzie ◽

John O. Miners

Keyword(s):

Fatty Acids ◽

Cytochrome P450 ◽

Human Liver ◽

Unsaturated Fatty Acids ◽

Cytochrome P450 2C9 ◽

In Vivo Extrapolation ◽

Long Chain

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Oncostatin M Promotes Differentiation of Fetal Hepatocytes in vitro and Regulates Liver Regeneration in vivo

Stem Cell and Liver Regeneration ◽

10.1007/978-4-431-53971-1_3 ◽

2004 ◽

pp. 26-35

Author(s):

Koji Nakamura ◽

Atsushi Miyajima

Keyword(s):

Liver Regeneration ◽

Oncostatin M ◽

Fetal Hepatocytes

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BMP-9 Modulates the Hepatic Responses to LPS

Cells ◽

10.3390/cells9030617 ◽

2020 ◽

Vol 9 (3) ◽

pp. 617

Author(s):

Haristi Gaitantzi ◽

Julius Karch ◽

Lena Germann ◽

Chen Cai ◽

Vanessa Rausch ◽

...

Keyword(s):

Liver Damage ◽

Human Liver ◽

Liver Sinusoidal Endothelial Cells ◽

Inflammatory Reactions ◽

Morphogenetic Protein ◽

Liver Fibrogenesis ◽

Nfkb Pathway ◽

Pre Treatment

It was previously shown that Bone Morphogenetic Protein (BMP)-9 is constitutively produced and secreted by hepatic stellate cells (HSC). Upon acute liver damage, BMP-9 expression is transiently down-regulated and blocking BMP-9 under conditions of chronic damage ameliorated liver fibrogenesis in C57BL/6 mice. Thereby, BMP-9 acted as a pro-fibrogenic cytokine in the liver but without directly activating isolated HSC in vitro. Lipopolysaccharide (LPS), an endotoxin derived from the membrane of Gram-negative bacteria in the gut, is known to be essential in the pathogenesis of diverse kinds of liver diseases. The aim of the present project was therefore to investigate how high levels of BMP-9 in the context of LPS signalling might result in enhanced liver damage. For this purpose, we stimulated human liver sinusoidal endothelial cells (LSEC) with LPS and incubated primary human liver myofibroblasts (MF) with the conditioned medium of these cells. We found that LPS led to the secretion of factors from LSEC that upregulate BMP-9 expression in MF. At least one of these BMP-9 enhancing factors was defined to be IL-6. High BMP-9 in turn, especially in combination with LPS stimulation, induced the expression of certain capillarization markers in LSEC and enhanced the LPS-mediated induction of pro-inflammatory cytokines in primary human macrophages. In LSEC, pre-treatment with BMP-9 reduced the LPS-mediated activation of the NfkB pathway, whereas in macrophages, LPS partially inhibited the BMP-9/Smad-1 signaling cascade. In vivo, in mice, BMP-9 led to the enhanced presence of F4/80-positive cells in the liver and it modulated the LPS-mediated regulation of inflammatory mediators. In summary, our data point to BMP-9 being a complex and highly dynamic modulator of hepatic responses to LPS: Initial effects of LPS on LSEC led to the upregulation of BMP-9 in MF but sustained high levels of BMP-9 in turn promote pro-inflammatory reactions of macrophages. Thereby, the spatial and timely fine-tuned presence (or absence) of BMP-9 is needed for efficient wound-healing responses in the liver.

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