scholarly journals Drug Repurposing in Alternative Medicine: Sochehwan, a Polyherbal Traditional Korean Digestant, Protects against Alcoholic Steatohepatitis by Regulating Cytochrome P450 2E1 Expression

Processes ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1760
Author(s):  
Ga-Ram Yu ◽  
Seung-Jun Lee ◽  
Dong-Woo Lim ◽  
Hyuck Kim ◽  
Jai-Eun Kim ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Liver Injury ◽  
Er Stress ◽  
Hepg2 Cells ◽  
Herbal Medicines ◽  
Drug Repurposing ◽  
Cytochrome P450 2E1 ◽  
Hepatic Enzyme ◽  
Cyp2e1 Expression

Sochehwan (SCH) is an herbal prescription from traditional oriental medicine and is currently used to treat digestive ailments. In a previous study, SCH was found to have the potential to attenuate metabolic syndrome (MetS) by activating AMPK and downstream signaling. From the view of drug repurposing, the efficacy of SCH on alcoholic liver injury is implied in classic medical texts but is yet to be proven. C57BL/6J mice were pre-treated with SCH orally for 5 days and challenged by providing a pair-fed Lieber DeCarli diet containing alcohol for 20 days. Hepatic enzyme and triglyceride levels and endoplasmic reticulum (ER) stress-related markers were analyzed. Moreover, mitogen-activated protein kinases (MAPKs) and cytochrome P450 2E1 (CYP2E1) levels were determined. CYP2E1-transfected HepG2 cells were used to test the cytoprotective efficacy of SCH against the adverse effects of alcohol in vitro. In mice, SCH administration notably reduced hepatic enzyme activity and neural lipid levels. Furthermore, ER-stress markers and MAPK phosphorylation were reduced due to ROS suppression, which was attributed to decreased CYP2E1 expression in liver tissue. In addition, SCH successfully protected CYP2E1-transfected HepG2 cells against ethanol. Our findings suggest SCH attenuated alcohol-induced liver injury by inhibiting CYP2E1 expression and indicate drug repurposing should be considered as a valuable option for drug development in traditional herbal medicines.

scholarly journals Metformin and Probiotics Interplay in Amelioration of Ethanol-Induced Oxidative Stress and Inflammatory Response in an In Vitro and In Vivo Model of Hepatic Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-31
Author(s):  
Farhin Patel ◽  
Kirti Parwani ◽  
Dhara Patel ◽  
Palash Mandal
Keyword(s):  
Oxidative Stress ◽  
Lipid Metabolism ◽  
Liver Injury ◽  
Inflammatory Response ◽  
Er Stress ◽  
Hepg2 Cells ◽  
Hepatic Injury ◽  
And Oxidative Stress

Alcohol-induced liver injury implicates inflammation and oxidative stress as important mediators. Despite rigorous research, there is still no Food and Drug Administration (FDA) approved therapies for any stage of alcoholic liver disease (ALD). Interestingly, metformin (Met) and several probiotic strains possess the potential of inhibiting alcoholic liver injury. Therefore, we investigated the effectiveness of combination therapy using a mixture of eight strains of lactic acid-producing bacteria, commercialized as Visbiome® (V) and Met in preventing the ethanol-induced hepatic injury using in vitro and in vivo models. Human HepG2 cells and male Wistar rats were exposed to ethanol and simultaneously treated with probiotic V or Met alone as well as in combination. Endoplasmic reticulum (ER) stress markers, inflammatory markers, lipid metabolism, reactive oxygen species (ROS) production, and oxidative stress were evaluated, using qRT-PCR, Oil red O staining, fluorimetry, and HPLC. In vitro, probiotic V and Met in combination prevented ethanol-induced cellular injury, ER stress, oxidative stress, and regulated lipid metabolism as well as inflammatory response in HepG2 cells. Probiotic V and Met also promoted macrophage polarization towards the M2 phenotype in ethanol-exposed RAW 264.7 macrophage cells. In vivo, combined administration of probiotic V and Met ameliorated the histopathological changes, inflammatory response, hepatic markers (liver enzymes), and lipid metabolism induced by ethanol. It also improved the antioxidant markers (HO-1 and Nrf-2), as seen by their protein levels in both HepG2 cells as well as liver tissue using ELISA. Hence, probiotic V may act, in addition to the Met, as an effective preventive treatment against ethanol-induced hepatic injury.

scholarly journals Comparative Proteomic Identification of Protein Disulphide Isomerase A6 Associated with Tert-Butylhydroperoxide-Induced Liver Injury in Rat Hepatocytes

2018 ◽  
Vol 45 (5) ◽  
pp. 1915-1926 ◽  
Author(s):  
Chien-Heng Shen ◽  
Shui-Yi Tung ◽  
Wen-Shih Huang ◽  
Kam-Fai Lee ◽  
Yung-Yu Hsieh ◽  
...  
Keyword(s):  
Liver Injury ◽  
Cell Viability ◽  
Er Stress ◽  
Primary Cultures ◽  
Liver Cells ◽  
Cytochrome C Release ◽  
Dapi Staining ◽  
Tert Butylhydroperoxide

Background/Aims: Oxidants are important human toxicants. They have been implicated in the occurrence and development of liver diseases. Increased intracellular tert-butylhydroperoxide (t-BHP) may be critical for oxidant toxicity, and is commonly used for evaluating mechanisms involving oxidative stress, but the method remains controversial. Methods: Primary cultures of hepatocytes as well as human Hep G2 and mouse FL83B liver cells were obtained. Cell viability was measured by annexin V–FITC/propidium iodide and DAPI staining to determine the effects of t-BHP treatment on acute liver injury. A proteomic assay provided information that was used to identify the differentially expressed proteins following t-BHP treatment; immunohistochemistry and western blotting were performed to detect the expression of PDIA6 activity in apoptotic and endoplasmic reticulum (ER) stress pathways. Results: Our results demonstrate that t-BHP treatment of liver cells increased cell cytotoxicity and the generation of reactive oxygen species. This treatment also increased the level of PDIA6; this was validated in vitro and in vivo based on a comparison of t-BHP-treated and -untreated groups. Treatment of mouse liver FL83B cells with t-BHP activated caspase 3, increased the expression of apoptotic molecules, caused cytochrome c release, and induced Bcl-2, Bax and IRE1α/TRAF2 complex formation. t-BHP-dependent induction of apoptosis was accompanied by sustained phosphorylation of the IRE1α/ASK1/JNK1/2/p38 pathways and PDIA6 expression. Furthermore, t-BHP induced liver FL83B cell viability and apoptosis by upregulating the levels of PDIA6; this process could be involved in the activation of the IRE1α/ASK1/JNK1/2/p38 signalling pathways. Conclusions: We conclude that t-BHP induced an apoptosis cascade and ER stress in hepatocytes by upregulation of PDIA6, providing a new mechanism underlying the effects of t-BHP on liver injury.

HepG2 cells as an in vitro model for evaluation of cytochrome P450 induction by xenobiotics

2014 ◽  
Vol 38 (5) ◽  
pp. 691-704 ◽  
Author(s):  
Jong Min Choi ◽  
Soo Jin Oh ◽  
Sang Yoon Lee ◽  
Ji Hye Im ◽  
Jung Min Oh ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Hepg2 Cells ◽  
In Vitro Model ◽  
Cytochrome P450 Induction ◽  
Vitro Model

Phenotyping of Cytochrome P450 2E1 In Vitro and In Vivo

2007 ◽  
Vol 8 (5) ◽  
pp. 493-498 ◽  
Author(s):  
Lena Ernstgard ◽  
Gunnar Johanson ◽  
Anne-Sophie Karlsson ◽  
Margareta Warholm
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 2E1

scholarly journals Down-Regulation of miR-212-5p Facilitates Homocysteine-Induced Hepatocytes Apoptosis Via Targeting PSMD10

2020 ◽  
Author(s):  
Huiping Zhang ◽  
Kun Xiao ◽  
Shengchao Ma ◽  
Long Xu ◽  
Ning Ding ◽  
...  
Keyword(s):  
Liver Injury ◽  
Er Stress ◽  
Underlying Mechanism ◽  
Luciferase Reporter ◽  
Down Regulation ◽  
Over Expression ◽  
Direct Binding ◽  
Induced Apoptosis ◽  
Insight Into

Abstract Background: Increasing evidences supported that elevated homocysteine (Hcy) levels contribute to cell apoptosis is implicated in the pathogenesis of liver injury, it correlates with liver disease severity. However, the underlying mechanism of apoptosis in Hcy-mediated liver injury remains obscure. Results: In this study, we found that homocysteine increases ER stress-mediated apoptosis and aggravates liver injury through up-regulation of PSMD10 expression in cbs+/- mice mice fed with high methionine diet and hepatocytes treated with homocysteine in vitro. Knockdown of PSMD10 expression remarkably reduced ER stress or apoptosis-associated protein in hepatocytes exposed to homocysteine. Moreover, bioinformatics analysis revealed that PSMD10 is a potential target gene of miR-212-5p, and luciferase reporter assay also confirmed that miR-212-5p negatively regulated PSMD10 expression by direct binding to its 3’-UTR regions. Subsequently, over-expression of miR-212-5p inhibited ER stress-mediated hepatocytes apoptosis though targeting PSMD10, all of which were abrogated by knockdown of miR-212-5p expression. Further study showed that the interaction between PSMD10 and GRP78 accelerated ER stress-mediated hepatic apoptosis induced by homocysteine. Conclusion: Taken together, these results demonstrated that down-regulation of miR-212-5p facilitates homocysteine-induced hepatocytes apoptosis via targeting PSMD10, which provides novel insight into the mechanism of homocysteine induced apoptosis in liver injury.

scholarly journals Physcion Protects Against Ethanol-Induced Liver Injury by Reprogramming of Circadian Clock

2020 ◽  
Vol 11 ◽  
Author(s):  
Youli Yao ◽  
Along Zuo ◽  
Qiyu Deng ◽  
Shikang Liu ◽  
Tianying Zhan ◽  
...  
Keyword(s):  
Liver Injury ◽  
Circadian Clock ◽  
Hepg2 Cells ◽  
Treatment Options ◽  
Potential Contribution ◽  
Protective Agent ◽  
Protective Effects ◽  
The Core ◽  
Metabolic Genes

The circadian clock plays a key role in our daily physiology and metabolism. Alcohol consumption disrupts the circadian rhythm of metabolic genes in the liver; however, the potential contribution of circadian clock modulation to alcoholic liver disease (ALD) is unknown. We identified a novel liver protective agent, physcion, which can alleviate fat accumulation and inflammation in ALD mice via reprogramming the hepatic circadian clock. The model of alcoholic hepatitis was established by intragastrically administering ethanol. In vitro, physcion was investigated by treating HepG2 cells with ethanol. The role of circadian clock in Physcion caused liver protection was tested by knocking down the core circadian gene Bmal1. Physcion application caused reduced lipogenesis and alleviated inflammation in alcohol-induced mice. In alcoholic hepatosteatosis models, physcion upregulated the core circadian genes. And the circadian misalignment triggered by ethanol was efficiently reversed by physcion. Physcion attenuated lipogenesis via reprogramming the circadian clock in HepG2 cells. Suppression of Bmal1 by RNA interference abolished the protective of physcion. In addition, Physcion binds to the active pocket of BMAL1 and promotes its expression. The study identified the novel liver protective effects of physcion on alcohol-induced liver injury, and modulation of the core circadian clock regulators contributes to ALD alleviation. More importantly, strategies targeting the circadian machinery, for example, Bmal1, may prove to be beneficial treatment options for this condition.

Sign in / Sign up

Export Citation Format

Share Document