scholarly journals Carbon monoxide-induced TFEB nuclear translocation enhances mitophagy/mitochondrial biogenesis in hepatocytes and ameliorates inflammatory liver injury

2018 ◽  
Vol 9 (11) ◽  
Author(s):  
Hyo Jeong Kim ◽  
Yeonsoo Joe ◽  
So-Young Rah ◽  
Seul-Ki Kim ◽  
Se-Ung Park ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Liver Injury ◽  
Mitochondrial Biogenesis ◽  
Nuclear Translocation

scholarly journals Energy determinants GAPDH and NDPK act as genetic modifiers for hepatocyte inclusion formation

2011 ◽  
Vol 195 (2) ◽  
pp. 217-229 ◽  
Author(s):  
Natasha T. Snider ◽  
Sujith V.W. Weerasinghe ◽  
Amika Singla ◽  
Jessica M. Leonard ◽  
Shinichiro Hanada ◽  
...  
Keyword(s):  
Liver Injury ◽  
Human Liver ◽  
Nuclear Translocation ◽  
Nucleoside Diphosphate Kinase ◽  
Isolated Hepatocytes ◽  
Dependent Manner ◽  
Genetic Modifiers ◽  
C3h Mice ◽  
Normal Human ◽  
Human Livers

Genetic factors impact liver injury susceptibility and disease progression. Prominent histological features of some chronic human liver diseases are hepatocyte ballooning and Mallory-Denk bodies. In mice, these features are induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) in a strain-dependent manner, with the C57BL and C3H strains showing high and low susceptibility, respectively. To identify modifiers of DDC-induced liver injury, we compared C57BL and C3H mice using proteomic, biochemical, and cell biological tools. DDC elevated reactive oxygen species (ROS) and oxidative stress enzymes preferentially in C57BL livers and isolated hepatocytes. C57BL livers and hepatocytes also manifested significant down-regulation, aggregation, and nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH). GAPDH knockdown depleted bioenergetic and antioxidant enzymes and elevated hepatocyte ROS, whereas GAPDH overexpression decreased hepatocyte ROS. On the other hand, C3H livers had higher expression and activity of the energy-generating nucleoside-diphosphate kinase (NDPK), and knockdown of hepatocyte NDPK augmented DDC-induced ROS formation. Consistent with these findings, cirrhotic, but not normal, human livers contained GAPDH aggregates and NDPK complexes. We propose that GAPDH and NDPK are genetic modifiers of murine DDC-induced liver injury and potentially human liver disease.

scholarly journals Hepatoprotective Effect of Polysaccharides Isolated from Dendrobium officinale against Acetaminophen-Induced Liver Injury in Mice via Regulation of the Nrf2-Keap1 Signaling Pathway

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Guosheng Lin ◽  
Dandan Luo ◽  
Jingjing Liu ◽  
Xiaoli Wu ◽  
Jinfen Chen ◽  
...  
Keyword(s):  
Liver Injury ◽  
Signaling Pathway ◽  
Nuclear Translocation ◽  
Hepatoprotective Effect ◽  
Dendrobium Officinale ◽  
Regulatory Subunit ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Glutamate Cysteine Ligase ◽  
Nrf2 Signaling Pathway

The effect of polysaccharides isolated from Dendrobium officinale (DOP) on acetaminophen- (APAP-) induced hepatotoxicity and the underlying mechanisms involved are investigated. Male Institute of Cancer Research (ICR) mice were randomly assigned to six groups: (1) control, (2) vehicle (APAP, 230 mg/kg), (3) N-acetylcysteine (100 mg/kg), (4) 50 mg/kg DOP, (5) 100 mg/kg DOP, and (6) 200 mg/kg DOP. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the serum and glutathione (GSH), malondialdehyde (MDA), catalase (CAT), total antioxidant capacity (T-AOC), myeloperoxidase (MPO), and reactive oxygen species (ROS) levels in the liver were determined after the death of the mice. The histological examination of the liver was also performed. The effect of DOP on the Kelch-like ECH-associated protein 1- (Keap1-) nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway was evaluated using Western blot analysis and real-time polymerase chain reaction (PCR). The results showed that DOP treatment significantly alleviated the hepatic injury. The decrease in ALT and AST levels in the serum and ROS, MDA, and MPO contents in the liver, as well as the increases in GSH, CAT, and T-AOC in the liver, were observed after DOP treatment. DOP treatment significantly induced the dissociation of Nrf2 from the Nrf2−Keap1 complex and promoted the Nrf2 nuclear translocation. Subsequently, DOP-mediated Nrf2 activation triggered the transcription and expressions of the glutamate–cysteine ligase catalytic (GCLC) subunit, glutamate–cysteine ligase regulatory subunit (GCLM), heme oxygenase-1 (HO-1), and NAD(P)H dehydrogenase quinone 1 (NQO1) in APAP-treated mice. The present study revealed that DOP treatment exerted potentially hepatoprotective effects against APAP-induced liver injury. Further investigation about mechanisms indicated that DOP exerted the hepatoprotective effect by suppressing the oxidative stress and activating the Nrf2−Keap1 signaling pathway.

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.

Inhalation of carbon monoxide prevents liver injury and inflammation following hind limb ischemia/reperfusion

2004 ◽  
Vol 19 (1) ◽  
pp. 106-108 ◽  
Author(s):  
Michael C. Ott ◽  
Jeffrey R. Scott ◽  
Aurelia Bihari ◽  
Amit Badhwar ◽  
Leo E. Otterbein ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Liver Injury ◽  
Hind Limb ◽  
Ischemia Reperfusion ◽  
Limb Ischemia ◽  
Hind Limb Ischemia

scholarly journals Cooperative effect of biliverdin and carbon monoxide on survival of mice in immune-mediated liver injury

Hepatology ◽  
2004 ◽  
Vol 40 (5) ◽  
pp. 1128-1135 ◽  
Author(s):  
Gabriele Sass ◽  
Stefan Seyfried ◽  
Miguel Parreira Soares ◽  
Kenichiro Yamashita ◽  
Elzbieta Kaczmarek ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Liver Injury ◽  
Cooperative Effect ◽  
Immune Mediated

Carbon Monoxide Rescues Mice from Lethal Sepsis by Supporting Mitochondrial Energetic Metabolism and Activating Mitochondrial Biogenesis

2009 ◽  
Vol 329 (2) ◽  
pp. 641-648 ◽  
Author(s):  
Steve Lancel ◽  
Sidi Mohamed Hassoun ◽  
Raphael Favory ◽  
Brigitte Decoster ◽  
Roberto Motterlini ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Mitochondrial Biogenesis ◽  
Energetic Metabolism ◽  
Lethal Sepsis

Canagliflozin Improves Liver Function in Rats by Upregulating Asparagine Synthetase

Pharmacology ◽  
2021 ◽  
pp. 1-10
Author(s):  
Shiqi Wang ◽  
Yasong Ding ◽  
Ruoyao Dong ◽  
Hongyun Wang ◽  
Lingdi Yin ◽  
...  
Keyword(s):  
Lactate Dehydrogenase ◽  
Liver Injury ◽  
Liver Function ◽  
Aspartate Aminotransferase ◽  
Alanine Aminotransferase ◽  
Nuclear Translocation ◽  
Asparagine Synthetase ◽  
Related Factor ◽  
Impaired Liver Function ◽  
Serum Alanine Aminotransferase

<b><i>Introduction:</i></b> Canagliflozin (CANA) is a sodium-glucose cotransporter 2 inhibitor that was recently approved for treating diabetes. However, its effects on liver function are not well understood. The function of asparagine synthetase (ASNS) has been studied in several cancers but not in liver injury. Therefore, we investigated the connection between CANA and ASNS in alleviating damage (i.e., their hepatoprotective effect) in a rat liver injury model. <b><i>Methods:</i></b> The rat model of liver injury was established using carbon tetrachloride treatment. Rats with liver injury were administered CANA orally for 8 weeks daily. After week 8, peripheral blood was collected to measure serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase levels. Liver histopathology was examined using hematoxylin and eosin staining to determine the degree of liver injury. Protein expression in the rat livers was examined using Western blotting. <b><i>Results:</i></b> CANA treatment decreased serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase levels compared with those of the untreated group, demonstrating diminished liver injury. Mechanistically, CANA treatment activated AMP-activated protein kinase (AMPK), leading to increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and activating transcription factor 4 (ATF4), which upregulated ASNS expression in liver-injured rats. <b><i>Conclusion:</i></b> CANA significantly alleviated liver injury by activating the AMPK/Nrf2/ATF4 axis and upregulating ASNS expression, indicating its potential for treating patients with type 2 diabetes mellitus with impaired liver function.

scholarly journals Columbianadin Dampens In Vitro Inflammatory Actions and Inhibits Liver Injury via Inhibition of NF-κB/MAPKs: Impacts on OH° Radicals and HO-1 Expression

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 553
Author(s):  
Thanasekaran Jayakumar ◽  
Shaw-Min Hou ◽  
Chao-Chien Chang ◽  
Tsorng-Harn Fong ◽  
Chih-Wei Hsia ◽  
...  
Keyword(s):  
Liver Injury ◽  
Signaling Pathways ◽  
Cell Activation ◽  
Nuclear Translocation ◽  
Biological Activities ◽  
Elevated Serum ◽  
Raw 264.7 Cells ◽  
Oh Radicals ◽  
No Production ◽  
Raw 264.7

Columbianadin (CBN), a natural coumarin isolated from Angelica decursiva, is reported to have numerous biological activities, including anticancer and platelet aggregation inhibiting properties. Here, we investigated CBN’s anti-inflammatory effect in lipopolysaccharide (LPS)-stimulated RAW 264.7 cell activation and deciphered the signaling process, which could be targeted by CBN as part of the mechanisms. Using a mouse model of LPS-induced acute liver inflammation, the CBN effects were examined by distinct histologic methods using trichrome, reticulin, and Weigert’s resorcin fuchsin staining. The result showed that CBN decreased LPS-induced expressions of TNF-α, IL-1β, and iNOS and NO production in RAW 264.7 cells and mouse liver. CBN inhibited LPS-induced ERK and JNK phosphorylation, increased IκBα levels, and inhibited NF-κB p65 phosphorylation and its nuclear translocation. Application of inhibitors for ERK (PD98059) and JNK (SP600125) abolished the LPS-induced effect on NF-κB p65 phosphorylation, which indicated that ERK and JNK signaling pathways were involved in CBN-mediated inhibition of NF-κB activation. Treatment with CBN decreased hydroxyl radical (OH°) generation and increased HO-1 expression in RAW 264.7 cells. Furthermore, LPS-induced liver injury, as indicated by elevated serum levels of liver marker enzymes (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) and histopathological alterations, were reversed by CBN. This work demonstrates the utility of CBN against LPS-induced inflammation, liver injury, and oxidative stress by targeting JNK/ERK and NF-κB signaling pathways.

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