scholarly journals The Potential Protective Effect of Oligoribonucleotides-d-Mannitol Complexes against Thioacetamide-Induced Hepatotoxicity in Mice

2018 ◽  
Vol 11 (3) ◽  
pp. 77 ◽  
Author(s):  
Tetiana Marchyshak ◽  
Tetiana Yakovenko ◽  
Igor Shmarakov ◽  
Zenoviy Tkachuk
Keyword(s):  
Liver Injury ◽  
Protective Effect ◽  
Transforming Growth Factor ◽  
Elevated Serum ◽  
Transforming Growth Factor Β1 ◽  
Hepatoprotective Activity ◽  
Protein Carbonyl ◽  
Glutathione S Transferase ◽  
Sh Group ◽  
Factor Α

This study investigated the potential hepatoprotective effect of oligoribonucleotides-d-mannitol complexes (ORNs-d-M) against thioacetamide (TAA)-induced hepatotoxicity in mice. The hepatoprotective activity of ORNs-d-M was evaluated in thioacetamide (TAA)-treated C57BL/6J. Results indicate that treatment with ORNs-d-M displayed a protective effect at the TAA-induced liver injury. Treatment with ORNs-d-M, starting at 0 h after the administration of TAA, decreased TAA-elevated serum alanine aminotransferase (ALT) and γ-glutamyl transpeptidase (GGT). Activities of glutathione S-transferase (GST) and glutathione peroxidase (GPx), and levels of glutathione (GSH), were enhanced with ORNs-d-M administration, while the hepatic oxidative biomarkers (TBA-reactive substances, protein carbonyl derivatives, protein-SH group) and myeloperoxidase (MPO) activity were reduced. Furthermore, genetic analysis has shown that the ORNs-d-M decreases the expression of mRNA pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6), profibrogenic cytokine-transforming growth factor β1 (TGF-β1), as well as the principal protein of the extracellular matrix—collagen I. The present study demonstrates that ORNs-d-M exerts a protective effect against TAA-induced liver injury, which may be associated with its anti-inflammatory effects, inhibition of overexpression of mRNA cytokines, and direct effects on the metabolism of the toxin.

Expression of Tumor Necrosis Factor-α and Transforming Growth Factor-β1 in Acute Liver Injury

1989 ◽  
Vol 1 (3) ◽  
pp. 219-226 ◽  
Author(s):  
Mark J. Czaja ◽  
Kathleen C. Flanders ◽  
Luis Biempica ◽  
Charna Klein ◽  
Mark A. Zern ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tumor Necrosis Factor ◽  
Liver Injury ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Transforming Growth Factor ◽  
Acute Liver Injury ◽  
Transforming Growth Factor Β1 ◽  
Factor Α ◽  
Necrosis Factor

scholarly journals Hepatoprotective Effect of the Fruits of Polygonum orientale L. Against Carbon Tetrachloride-Induced Liver Fibrosis in Mice

2020 ◽  
Vol 15 (11) ◽  
pp. 1934578X2097150
Author(s):  
Yung-Jia Chiu ◽  
Kun-Chang Wu ◽  
Jen-Chieh Tsai ◽  
Chun-Pin Kao ◽  
Jung Chao ◽  
...  
Keyword(s):  
Carbon Tetrachloride ◽  
Growth Factor ◽  
Liver Injury ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Serum Levels ◽  
Hepatoprotective Activity ◽  
Tissue Growth ◽  
Factor Α

The aim of this study was to evaluate the hepatoprotective effects of the fruits of Polygonum orientale L. (POE) against fibrosis in carbon tetrachloride (CCl4)-induced liver injury. Bioactive components of POE were identified using liquid chromatography (LC)-mass spectrometry (MS)/MS by comparison with standards. Treatment with either silymarin (200 mg/kg) or POE (0.5 and 1.0 g/kg) caused significant decreases in the serum levels of enzymes and reduced the extent of liver lesions and fibrosis in histological analysis. POE (0.5 and 1.0 g/kg) decreased the levels of malondialdehyde, nitric oxide, proinflammatory cytokines (ie, tumor necrosis factor-α, interleukin [IL]-1β, and IL-6), an inflammatory cytokine (ie, cyclooxygenase-2), a profibrotic cytokine (ie, transforming growth factor-β), and fibrosis-related proteins (ie, connective tissue growth factor and α-smooth muscle actin) in the liver and enhanced the activities of the antioxidative enzymes superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. Quantitative analysis of the active constituents in POE revealed an extract composition of 3.4 mg/g of protocatechuic acid, 20.8 mg/g of taxifolin, and 5.6 mg/g of quercetin. We have demonstrated that the hepatoprotective mechanisms of POE are likely to be associated with the decrease in inflammatory cytokines by increasing the activities of antioxidant enzymes. Our findings provide evidence that POE possesses a hepatoprotective activity to ameliorate chronic liver injury.

Targeting ER protein TXNDC5 in hepatic stellate cell mitigates liver fibrosis by repressing non-canonical TGFβ signalling

Gut ◽  
2021 ◽  
pp. gutjnl-2021-325065
Author(s):  
Chen-Ting Hung ◽  
Tung-Hung Su ◽  
Yen-Ting Chen ◽  
Yueh-Feng Wu ◽  
You-Tzung Chen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Liver Fibrosis ◽  
Liver Injury ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Transforming Growth Factor Β1 ◽  
Duct Ligation ◽  
Extracellular Matrix Production ◽  
Matrix Production

Background and objectivesLiver fibrosis (LF) occurs following chronic liver injuries. Currently, there is no effective therapy for LF. Recently, we identified thioredoxin domain containing 5 (TXNDC5), an ER protein disulfide isomerase (PDI), as a critical mediator of cardiac and lung fibrosis. We aimed to determine if TXNDC5 also contributes to LF and its potential as a therapeutic target for LF.DesignHistological and transcriptome analyses on human cirrhotic livers were performed. Col1a1-GFPTg, Alb-Cre;Rosa26-tdTomato and Tie2-Cre/ERT2;Rosa26-tdTomato mice were used to determine the cell type(s) where TXNDC5 was induced following liver injury. In vitro investigations were conducted in human hepatic stellate cells (HSCs). Col1a2-Cre/ERT2;Txndc5fl/fl (Txndc5cKO) and Alb-Cre;Txndc5fl/fl (Txndc5Hep-cKO) mice were generated to delete TXNDC5 in HSCs and hepatocytes, respectively. Carbon tetrachloride treatment and bile duct ligation surgery were employed to induce liver injury/fibrosis in mice. The extent of LF was quantified using histological, imaging and biochemical analyses.ResultsTXNDC5 was upregulated markedly in human and mouse fibrotic livers, particularly in activated HSC at the fibrotic foci. TXNDC5 was induced by transforming growth factor β1 (TGFβ1) in HSCs and it was both required and sufficient for the activation, proliferation, survival and extracellular matrix production of HSC. Mechanistically, TGFβ1 induces TXNDC5 expression through increased ER stress and ATF6-mediated transcriptional regulation. In addition, TXNDC5 promotes LF by redox-dependent JNK and signal transducer and activator of transcription 3 activation in HSCs through its PDI activity, activating HSCs and making them resistant to apoptosis. HSC-specific deletion of Txndc5 reverted established LF in mice.ConclusionsER protein TXNDC5 promotes LF through redox-dependent HSC activation, proliferation and excessive extracellular matrix production. Targeting TXNDC5, therefore, could be a potential novel therapeutic strategy to ameliorate LF.

scholarly journals Hypothermia Advocates Functional Mitochondria and Alleviates Oxidative Stress to Combat Acetaminophen-Induced Hepatotoxicity

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2354
Author(s):  
Yeong Lan Tan ◽  
Han Kiat Ho
Keyword(s):  
Liver Injury ◽  
Mitochondrial Biogenesis ◽  
Transforming Growth Factor ◽  
Antioxidant Response ◽  
Moderate Hypothermia ◽  
Transforming Growth Factor Α ◽  
High Prevalence ◽  
Mouse Hepatocytes ◽  
Factor Α ◽  
Jnk Activation

For years, moderate hypothermia (32 °C) has been proposed as an unorthodox therapy for liver injuries, with proven hepatoprotective potential. Yet, limited mechanistic understanding has largely denied its acceptance over conventional pharmaceuticals for hepatoprotection. Today, facing a high prevalence of acetaminophen-induced liver injury (AILI) which accounts for the highest incidence of acute liver failure, hypothermia was evaluated as a potential therapy to combat AILI. For which, transforming growth factor-α transgenic mouse hepatocytes (TAMH) were subjected to concomitant 5 mM acetaminophen toxicity and moderate hypothermic conditioning for 24 h. Thereafter, its impact on mitophagy, mitochondrial biogenesis, glutathione homeostasis and c-Jun N-terminal kinase (JNK) signaling pathways were investigated. In the presence of AILI, hypothermia displayed simultaneous mitophagy and mitochondrial biogenesis to conserve functional mitochondria. Furthermore, antioxidant response was apparent with higher glutathione recycling and repressed JNK activation. These effects were, however, unremarkable with hypothermia alone without liver injury. This may suggest an adaptive response of hypothermia only to the injured sites, rendering it favorable as a potential targeted therapy. In fact, its cytoprotective effects were displayed in other DILI of similar pathology as acetaminophen i.e., valproate- and diclofenac-induced liver injury and this further corroborates the mechanistic findings of hypothermic actions on AILI.

scholarly journals Acute Liver Injury after CCl4 Administration Is Independent of Smad7 Expression in Myeloid Cells

2019 ◽  
Vol 20 (22) ◽  
pp. 5528 ◽  
Author(s):  
Jessica Endig ◽  
Ludmilla Unrau ◽  
Paulina Sprezyna ◽  
Sebasting Rading ◽  
Meliha Karsak ◽  
...  
Keyword(s):  
Liver Injury ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Elevated Serum ◽  
Myeloid Cells ◽  
Transforming Growth Factor Β ◽  
Cellular Processes ◽  
Ccl4 Administration ◽  
Smad7 Expression ◽  
The Impact

Myeloid cells are essential for the initiation and termination of innate and adaptive immunity that create homeostasis in the liver. Smad7 is an inhibitor of the transforming growth factor β (TGF-β) signaling pathway, which regulates inflammatory cellular processes. Knockdown of Smad7 in hepatocytes has been shown to promote liver fibrosis, but little is known about the effects of Smad7 in myeloid cells during inflammatory responses in the liver. Using mice with a myeloid-specific knockdown of Smad7 (LysM-Cre Smad7fl/fl), we investigated the impact of Smad7 deficiency in myeloid cells on liver inflammation and regeneration using the well-established model of CCl4-mediated liver injury. Early (24/48 h) and late (7 d) time points were analyzed. We found that CCl4 induces severe liver injury, with elevated serum ALT levels, centrilobular and periportal necrosis, infiltrating myeloid cells and an increase of inflammatory cytokines in the liver. Furthermore, as expected, inflammation peaked at 24 h and subsided after 7 d. However, the knockdown of Smad7 in myeloid cells did not affect any of the investigated parameters in the CCl4-treated animals. In summary, our results suggest that the inhibition of TGF-β signaling via Smad7 expression in myeloid cells is dispensable for the induction and control of acute CCl4-induced liver injury.

scholarly journals S-Adenosylmethionine attenuates the lipopolysaccharide-induced expression of the gene for tumour necrosis factor α

1999 ◽  
Vol 342 (1) ◽  
pp. 21-25 ◽  
Author(s):  
Walter H. WATSON ◽  
Yanming ZHAO ◽  
Rajender K. CHAWLA
Keyword(s):  
Liver Injury ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Elevated Serum ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Tumour Necrosis Factor Α ◽  
Tnf Gene ◽  
Factor Α ◽  
Necrosis Factor

Intracellular deficiency of S-adenosylmethionine (AdoMet) and elevated serum concentrations of tumour necrosis factor α (TNF) are hallmarks of toxin-induced liver injury. In these models, the administration of either exogenous AdoMet or antibody/soluble receptor for TNF attenuates the injury. We have demonstrated previously that the administration of exogenous AdoMet to AdoMet-deficient rats attenuated lipopolysaccharide (LPS)-induced liver injury and serum TNF concentrations. Here we report that AdoMet lowered the amount of TNF secreted by LPS-stimulated murine macrophage cells (RAW 264.7) in a dose-dependent manner. The inhibition of TNF release was correlated with changes in the steady-state TNF mRNA concentrations. Changes in TNF mRNA were not due to its altered stability and might have been due to an attenuation of the transcription rate of the TNF gene. The inhibition of TNF release in RAW cells was not mediated by GSH because treatment with AdoMet did not increase intracellular GSH. In addition, N-acetylcysteine, whereas it did increase GSH concentration, had no effect on LPS-stimulated TNF release in these cells. Exogenous AdoMet also attenuated LPS-induced serum TNF levels in normal rats sensitized with lead. Thus AdoMet administration might exert its hepatoprotective effects at least in part by its inhibitory effect on expression of the gene for TNF.

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