Ginsenoside Rb1, A Major Saponin from Panax ginseng, Exerts Protective Effects Against Acetaminophen-Induced Hepatotoxicity in Mice

2019 ◽  
Vol 47 (08) ◽  
pp. 1815-1831 ◽  
Author(s):  
Shen Ren ◽  
Jing Leng ◽  
Xing-Yue Xu ◽  
Shuang Jiang ◽  
Ying-Ping Wang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Panax Ginseng ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Protective Effects ◽  
Ginsenoside Rb1 ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Oxide Synthase

Acute liver injury (ALI) induced by acetaminophen (APAP) is the main cause of drug-induced liver injury. Previous reports indicated liver failure could be alleviated by saponins (ginsenosides) from Panax ginseng against APAP-induced inflammatory responses in vivo. However, validation towards ginsenoside Rb1 as a major and marker saponin may protect liver from APAP-induced ALI and its mechanisms are poorly elucidated. In this study, the protective effects and the latent mechanisms of Rb1 action against APAP-induced hepatotoxicity were investigated. Rb1 was administered orally with 10[Formula: see text]mg/kg and 20[Formula: see text]mg/kg daily for 1 week before a single injection of APAP (250[Formula: see text]mg/kg, i.p.) 1[Formula: see text]h after the last treatment of Rb1. Serum alanine/aspartate aminotransferases (ALT/AST), liver glutathione (GSH) depletion, as well as the inflammatory cytokines, such as tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text]), interleukin-1[Formula: see text] (IL-1[Formula: see text]), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), were analyzed to indicate the underlying protective effects of Rb1 against APAP-induced hepatotoxicity with significant inflammatory responses. Histological examination further proved Rb1’s protective effects. Importantly, Rb1 mitigated the changes in the phosphorylation of MAPK and PI3K/Akt, as well as its downstream factor NF-[Formula: see text]B. In conclusion, experimental data clearly demonstrated that Rb1 exhibited a remarkable liver protective effect against APAP-induced ALI, partly through regulating MAPK and PI3K/Akt signaling pathways-mediated inflammatory responses.

Drug-induced liver injury classification model based on in vitro human transcriptomics and in vivo rat clinical chemistry data

2014 ◽  
Vol 2 (4) ◽  
pp. 63-70 ◽  
Author(s):  
Danyel Jennen ◽  
Jan Polman ◽  
Mark Bessem ◽  
Maarten Coonen ◽  
Joost van Delft ◽  
...  
Keyword(s):  
Liver Injury ◽  
Clinical Chemistry ◽  
Classification Model ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Chemistry Data ◽  
Model Based ◽  
Injury Classification

Lighting up alkaline phosphatase in drug-induced liver injury using a new chemiluminescence resonance energy transfer nanoprobe

2018 ◽  
Vol 54 (88) ◽  
pp. 12479-12482 ◽  
Author(s):  
Xueting Liu ◽  
Nannan Fan ◽  
Lijie Wu ◽  
Chuanchen Wu ◽  
Yongqing Zhou ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Energy Transfer ◽  
Liver Injury ◽  
Alkaline Phosphatase Level ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Drug Induced ◽  
Drug Induced Liver Injury

Ultra-sensitive imaging of the alkaline phosphatase levelin vivoin drug-induced liver injury with a new chemiluminescence resonance energy transfer nanoprobe.

Zucker Lean Rats With Hepatic Steatosis Recapitulate Asymptomatic Metabolic Syndrome and Exhibit Greater Sensitivity to Drug-Induced Liver Injury Compared With Standard Nonclinical Sprague-Dawley Rat Model

2020 ◽  
Vol 48 (8) ◽  
pp. 994-1007
Author(s):  
Timothy P. LaBranche ◽  
Anna K. Kopec ◽  
Srinivasa R. Mantena ◽  
Brett D. Hollingshead ◽  
Andrew W. Harrington ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Pharmaceutical Industry ◽  
Liver Injury ◽  
Hepatic Steatosis ◽  
Sprague Dawley ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Sd Rats ◽  
Normal Chow

Fatty liver disease is a potential risk factor for drug-induced liver injury (DILI). Despite advances in nonclinical in vitro and in vivo models to assess liver injury during drug development, the pharmaceutical industry is still plagued by idiosyncratic DILI. Here, we tested the hypothesis that certain features of asymptomatic metabolic syndrome (namely hepatic steatosis) increase the risk for DILI in certain phenotypes of the human population. Comparison of the Zucker Lean (ZL) and Zucker Fatty rats fed a high fat diet (HFD) revealed that HFD-fed ZL rats developed mild hepatic steatosis with compensatory hyperinsulinemia without increases in liver enzymes. We then challenged steatotic HFD-fed ZL rats and Sprague-Dawley (SD) rats fed normal chow, a nonclinical model widely used in the pharmaceutical industry, with acetaminophen overdose to induce liver injury. Observations in HFD-fed ZL rats included increased liver injury enzymes and greater incidence and severity of hepatic necrosis compared with similarly treated SD rats. The HFD-fed ZL rats also had disproportionately higher hepatic drug accumulation, which was linked with abnormal hepatocellular efflux transporter distribution. Here, we identify ZL rats with HFD-induced hepatic steatosis as a more sensitive nonclinical in vivo test system for modeling DILI compared with SD rats fed normal chow.

scholarly journals Current Perspective: 3D Spheroid Models Utilizing Human-Based Cells for Investigating Metabolism-Dependent Drug-Induced Liver Injury

2020 ◽  
Vol 2 ◽  
Author(s):  
Christopher R. Cox ◽  
Stephen Lynch ◽  
Christopher Goldring ◽  
Parveen Sharma
Keyword(s):  
Liver Injury ◽  
Pharmaceutical Companies ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Current Perspective ◽  
Dosing Regimens ◽  
Underlying Mechanisms ◽  
Approved Drugs

Drug-induced liver injury (DILI) remains a leading cause for the withdrawal of approved drugs. This has significant financial implications for pharmaceutical companies, places increasing strain on global health services, and causes harm to patients. For these reasons, it is essential that in-vitro liver models are capable of detecting DILI-positive compounds and their underlying mechanisms, prior to their approval and administration to patients or volunteers in clinical trials. Metabolism-dependent DILI is an important mechanism of drug-induced toxicity, which often involves the CYP450 family of enzymes, and is associated with the production of a chemically reactive metabolite and/or inefficient removal and accumulation of potentially toxic compounds. Unfortunately, many of the traditional in-vitro liver models fall short of their in-vivo counterparts, failing to recapitulate the mature hepatocyte phenotype, becoming metabolically incompetent, and lacking the longevity to investigate and detect metabolism-dependent DILI and those associated with chronic and repeat dosing regimens. Nevertheless, evidence is gathering to indicate that growing cells in 3D formats can increase the complexity of these models, promoting a more mature-hepatocyte phenotype and increasing their longevity, in vitro. This review will discuss the use of 3D in vitro models, namely spheroids, organoids, and perfusion-based systems to establish suitable liver models to investigate metabolism-dependent DILI.

scholarly journals TAMH: A Useful In Vitro Model for Assessing Hepatotoxic Mechanisms

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Madison Davis ◽  
Brendan D. Stamper
Keyword(s):  
Liver Injury ◽  
Transforming Growth Factor ◽  
Chemical Exposure ◽  
Health Concern ◽  
Hepatocellular Injury ◽  
Drug Induced ◽  
Endogenous Factors ◽  
Drug Induced Liver Injury

In vitro models for hepatotoxicity can be useful tools to predict in vivo responses. In this review, we discuss the use of the transforming growth factor-αtransgenic mouse hepatocyte (TAMH) cell line, which is an attractive model to study drug-induced liver injury due to its ability to retain a stable phenotype and express drug-metabolizing enzymes. Hepatotoxicity involves damage to the liver and is often associated with chemical exposure. Since the liver is a major site for drug metabolism, drug-induced liver injury is a serious health concern for certain agents. At the molecular level, various mechanisms may protect or harm the liver during drug-induced hepatocellular injury including signaling pathways and endogenous factors (e.g., Bcl-2, GSH, Nrf2, or MAPK). The interplay between these and other pathways in the hepatocyte can change upon drug or drug metabolite exposure leading to intracellular stress and eventually cell death and liver injury. This review focuses on mechanistic studies investigating drug-induced toxicity in the TAMH line and how alterations to hepatotoxic mechanisms in this model relate to the in vivo situation. The agents discussed herein include acetaminophen (APAP), tetrafluoroethylcysteine (TFEC), flutamide, PD0325901, lapatinib, and flupirtine.

scholarly journals miR-15a-3p Protects Against Isoniazid-Induced Liver Injury via Suppressing N-Acetyltransferase 2 Expression

2021 ◽  
Vol 8 ◽  
Author(s):  
Xinmei Li ◽  
Heng Zhang ◽  
Lin Xu ◽  
Yuan Jin ◽  
Jiao Luo ◽  
...  
Keyword(s):  
Liver Injury ◽  
Drug Efficacy ◽  
Mature Mirnas ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Expression Activity ◽  
Underlying Mechanisms ◽  
Line Drug

Isoniazid (INH), an effective first-line drug for tuberculosis treatment, has been reported to be associated with hepatotoxicity for decades, but the underlying mechanisms are poorly understood. N-acetyltransferase 2 (NAT2) is a Phase II enzyme that specifically catalyzes the acetylation of INH, and NAT2 expression/activity play pivotal roles in INH metabolism, drug efficacy, and toxicity. In this study, we systematically investigated the regulatory roles of microRNA (miRNA) in NAT2 expression and INH-induced liver injury via a series of in silico, in vitro, and in vivo analyses. Four mature miRNAs, including hsa-miR-15a-3p, hsa-miR-628-5p, hsa-miR-1262, and hsa-miR-3132, were predicted to target the NAT2 transcript, and a negative correlation was observed between hsa-miR-15a-3p and NAT2 transcripts in liver samples. Further experiments serially revealed that hsa-miR-15a-3p was able to interact with the 3′-untranslated region (UTR) of NAT2 directly, suppressed the endogenous NAT2 expression, and then inhibited INH-induced NAT2 overexpression as well as INH-induced liver injury, both in liver cells and mouse model. In summary, our results identified hsa-miR-15a-3p as a novel epigenetic factor modulating NAT2 expression and as a protective module against INH-induced liver injury, and provided new clues to elucidate the epigenetic regulatory mechanisms concerning drug-induced liver injury (DILI).

scholarly journals Predicting Drug-Induced Liver Injury Using Convolutional Neural Network and Molecular Fingerprint-Embedded Features

2021 ◽  
Author(s):  
TH Nguyen-Vo ◽  
L Nguyen ◽  
N Do ◽  
PH Le ◽  
TN Nguyen ◽  
...  
Keyword(s):  
Liver Injury ◽  
Language Processing ◽  
American Chemical Society ◽  
In Vivo Studies ◽  
Drug Induced ◽  
Molecular Fingerprint ◽  
Molecular Fingerprints ◽  
Safety Testing ◽  
Drug Induced Liver Injury

© 2020 American Chemical Society. As a critical issue in drug development and postmarketing safety surveillance, drug-induced liver injury (DILI) leads to failures in clinical trials as well as retractions of on-market approved drugs. Therefore, it is important to identify DILI compounds in the early-stages through in silico and in vivo studies. It is difficult using conventional safety testing methods, since the predictive power of most of the existing frameworks is insufficiently effective to address this pharmacological issue. In our study, we employ a natural language processing (NLP) inspired computational framework using convolutional neural networks and molecular fingerprint-embedded features. Our development set and independent test set have 1597 and 322 compounds, respectively. These samples were collected from previous studies and matched with established chemical databases for structural validity. Our study comes up with an average accuracy of 0.89, Matthews's correlation coefficient (MCC) of 0.80, and an AUC of 0.96. Our results show a significant improvement in the AUC values compared to the recent best model with a boost of 6.67%, from 0.90 to 0.96. Also, based on our findings, molecular fingerprint-embedded featurizer is an effective molecular representation for future biological and biochemical studies besides the application of classic molecular fingerprints.

scholarly journals Ginsenoside Rb1 Alleviates Alcohol-Induced Liver Injury by Inhibiting Steatosis, Oxidative Stress, and Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuqi Lai ◽  
Qinxiang Tan ◽  
Shu Xv ◽  
Sha Huang ◽  
Yuhua Wang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Nile Red ◽  
Neutrophil Infiltration ◽  
Liver Parenchyma ◽  
Lipid Deposition ◽  
Protective Effects ◽  
Panax Quinquefolium ◽  
Ginsenoside Rb1 ◽  
Factor Α

Alcoholic liver disease (ALD) has become a heavy burden on health worldwide. Ginsenoside Rb1 (GRb1), extracted from Panax quinquefolium L., has protective effects on many diseases, but the effect and mechanisms of GRb1 on ALD remain unknown. This study aimed to investigate the protective effects of GRb1 on ALD and to discover the potential mechanisms. Zebrafish larvae were exposed to 350 mM ethanol for 32 h to establish a model of acute alcoholic liver injury, and the larvae were then treated with 6.25, 12.5, or 25 μM GRb1 for 48 h. The human hepatocyte cell line was stimulated by 100 mM ethanol and meanwhile incubated with 6.25, 12.5, and 25 μM GRb1 for 24 h. The lipid changes were detected by Oil Red O staining, Nile Red staining, and triglyceride determination. The antioxidant capacity was assessed by fluorescent probes in vivo, and the expression levels of inflammatory cytokines were detected by immunohistochemistry, immunofluorescence, and quantitative real-time PCR. The results showed that GRb1 alleviated lipid deposition in hepatocytes at an optimal concentration of 12.5 μM in vivo. GRb1 reversed the reactive oxygen species accumulation caused by alcohol consumption and partially restored the level of glutathione. Furthermore, GRb1 ameliorated liver inflammation by inhibiting neutrophil infiltration in the liver parenchyma and downregulating the expression of nuclear factor-kappa B pathway-associated proinflammatory cytokines, including tumor necrosis factor-α and interleukin-1β. This study revealed that GRb1 has a protective effect on alcohol-induced liver injury due to its resistance to lipid deposition as well as antioxidant and anti-inflammatory actions. These findings suggest that GRb1 may be a promising candidate against ALD.

Sign in / Sign up

Export Citation Format

Share Document