• COX-2
• Celecoxib
• Concanavalin A
• HO-1
• Nrf2
• p-JNK

Ferroptosis represents a typical process that has dual functions in cell fate decisions since the reduction and/or inhibition of ferroptosis is desirable for the therapies of diseases such as neurological disorders, localized ischemia-reperfusion, kidney injury, and hematological diseases, while the enhanced ferroptosis of cancer cells may benefit patients with cancer. The JNK pathway also has a real dual function in the fate of cells. Multiple factors suggest a potential link between the ferroptotic and JNK pathways; (i) both processes are ROS mediated; (ii) both can be inhibited by lipid peroxide scavengers; (iii) RAS mutations may play a role in the initiation of both pathways. We aimed to investigate the possible link between ferroptosis and the JNK pathway. Interestingly, JNK inhibitor co-treatment could enhance the cancer cytotoxic effect of the ferroptosis inducers in NRAS and KRAS mutation-harboring cells (HT-1080 and MIA PaCa-2). Since cancer’s cytotoxic effect from the JNK inhibitors could only be suspended by the ferroptosis inhibitors, and that sole JNK-inhibitor treatment did not affect cell viability, it seems that the JNK inhibitors “just” amplify the effect of the ferroptosis inducers. This cancer cell death amplifying effect of the JNK inhibitors could not be observed in other oxidative stress-driven cell deaths. Hence, it seems it is specific to ferroptosis. Finally, our results suggest that GSH content/depletion could be an important candidate for switching the anti-cancer effect of JNK inhibitors.

• Antineoplastic Agents/pharmacology
• Ferroptosis
• Humans
• Lipid Peroxides
• MAP Kinase Signaling System
• Neoplasms/metabolism
• Proto-Oncogene Proteins p21(ras)/genetics
• Proto-Oncogene Proteins p21(ras)/metabolism
• Reactive Oxygen Species/metabolism

• Inflammation
• Insulin resistance
• NAFLD
• Nonalcoholic fatty liver disease
• Polyphenols
• Resveratrol

Dexmedetomidine [DEX; (S)-4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole] is a selective α₂-adrenergic receptor (α₂-AR) agonist that attenuates the liver damage associated with local or systemic inflammation. However, it remains unclear whether DEX has protective effects against acetaminophen (Paracetamol, PARA)-induced liver toxicity (PILT).

PILT mice were established by intraperitoneal administration of a hepatotoxic dose of acetaminophen (300 mg/kg). Thirty minutes later, the mice were treated with DEX at a concentration of 0, 5, 25, or 50 μg/kg. Blood and liver samples were obtained for further analysis.

DEX treatment significantly attenuated PILT in mice, with the strongest beneficial effects at a dose of 25 μg/kg. The levels of hepatic cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), in addition to myeloperoxidase (MPO) activity, were significantly decreased following DEX treatment. Moreover, DEX treatment reduced macrophage recruitment around the area of hepatotoxicity and the expression levels of hepatic phosphorylated mitogen-activated protein kinase kinase 4 (MAP2K4), c-jun N-terminal kinase (JNK), and c-Jun expression induced by acetaminophen overdose.

The data suggest that DEX likely downregulates the JNK signaling pathway and its downstream effectors to promote its hepatoprotective effect, providing a clinical application of DEX for the attenuation of PILT.

• MAP2K4/JNK/c-Jun
• acetaminophen-induced liver toxicity
• dexmedetomidine

Non-alcoholic fatty liver disease (NAFLD) has become an epidemic largely due to the worldwide increase in obesity. While lifestyle modifications and pharmacotherapies have been used to alleviate NAFLD, successful treatment options are limited. One of the main barriers to finding safe and effective drugs for long-term use in NAFLD is the fast initiation and progression of disease in the available preclinical models. Therefore, we are in need of preclinical models that (1) mimic the human manifestation of NAFLD and (2) have a longer progression time to allow for the design of superior treatments.

To characterize a model of prolonged high-fat diet (HFD) feeding for investigation of the long-term progression of NAFLD.

In this study, we utilized prolonged HFD feeding to examine NAFLD features in C57BL/6 male mice. We fed mice with a HFD (60% fat, 20% protein, and 20% carbohydrate) for 80 wk to promote obesity (Old-HFD group, n = 18). A low-fat diet (LFD) (14% fat, 32% protein, and 54% carbohydrate) was administered for the same duration to age-matched mice (Old-LFD group, n = 15). An additional group of mice was maintained on the LFD (Young-LFD, n = 20) for a shorter duration (6 wk) to distinguish between age-dependent and age-independent effects. Liver, colon, adipose tissue, and feces were collected for histological and molecular assessments.

Prolonged HFD feeding led to obesity and insulin resistance. Histological analysis in the liver of HFD mice demonstrated steatosis, cell injury, portal and lobular inflammation and fibrosis. In addition, molecular analysis for markers of endoplasmic reticulum stress established that the liver tissue of HFD mice have increased phosphorylated Jnk and CHOP. Lastly, we evaluated the gut microbial composition of Old-LFD and Old-HFD. We observed that prolonged HFD feeding in mice increased the relative abundance of the Firmicutes phylum. At the genus level, we observed a significant increase in the abundance of Adercreutzia, Coprococcus, Dorea, and Ruminococcus and decreased relative abundance of Turicibacter and Anaeroplasma in HFD mice.

Overall, these data suggest that chronic HFD consumption in mice can mimic pathophysiological and some microbial events observed in NAFLD patients.

• High-fat diet
• Obesity
• Non-alcoholic fatty liver disease
• Gut microbiome
• Endoplasmic reticulum stress
• Inflammation
• Fibrosis

• K99 AT009206 NCCIH NIH HHS
• R00 AT009206 NCCIH NIH HHS

• Immunity
• Inflammation and apoptosis
• Lateolabrax japonicas
• Liver disease
• Metabolic disorder
• cAMP-JNK/NF-kB-caspase

• Animal Feed/analysis
• Animal Feed/classification
• Animals
• Basal Metabolism
• Bass/growth & development
• Diet/classification
• Diet/veterinary
• Fatty Liver/chemically induced
• Fatty Liver/physiopathology
• Fatty Liver/veterinary
• Fish Diseases/chemically induced
• Fish Diseases/physiopathology
• Liver/physiology
• Liver/physiopathology
• Metabolic Diseases/chemically induced
• Metabolic Diseases/physiopathology
• Metabolic Diseases/veterinary
• Plant Proteins, Dietary/administration & dosage
• Plant Proteins, Dietary/metabolism
• Signal Transduction/drug effects

• hepatocytes
• cell death
• mitochondria
• liver injury
• pdk4

• Fibrosis
• Genetic factors
• Inflammation
• Nonalcoholic fatty liver disease (NAFLD)
• Nonalcoholic steatohepatitis (NASH)

• alcoholic liver disease
• galactosamine
• pentamidine
• tumor necrosis factor
• vlx103

Liver failure induced by systemic inflammatory response (SIRS) is often associated with mitochondrial dysfunction but the mechanism linking SIRS and mitochondria-mediated liver failure is still a matter of discussion. Current hypotheses suggest that causative events could be a drop in ATP synthesis, opening of mitochondrial permeability transition pore, specific changes in mitochondrial morphology, impaired Ca²⁺ uptake, generation of mitochondrial reactive oxygen species (mtROS), turnover of mitochondria and imbalance in electron supply to the respiratory chain. The aim of this review is to critically analyze existing hypotheses, in order to highlight the most promising research lines helping to prevent liver failure induced by SIRS. Evaluation of the literature shows that there is no consistent support that impaired Ca⁺⁺ metabolism, electron transport chain function and ultrastructure of mitochondria substantially contribute to liver failure. Moreover, our analysis suggests that the drop in ATP levels has protective rather than a deleterious character. Recent data suggest that the most critical mitochondrial event occurring upon SIRS is the release of mtROS in cytoplasm, which can activate two specific intracellular signaling cascades. The first is the mtROS-mediated activation of NADPH-oxidase in liver macrophages and endothelial cells; the second is the acceleration of the expression of inflammatory genes in hepatocytes. The signaling action of mtROS is strictly controlled in mitochondria at three points, (i) at the site of ROS generation at complex I, (ii) the site of mtROS release in cytoplasm via permeability transition pore, and (iii) interaction with specific kinases in cytoplasm. The systems controlling mtROS-signaling include pro- and anti-inflammatory mediators, nitric oxide, Ca²⁺ and NADPH-oxidase. Analysis of the literature suggests that further research should be focused on the impact of mtROS on organ failure induced by inflammation and simultaneously providing a new theoretical basis for a targeted therapy of overwhelmed inflammatory response.

•

Relationship between mitochondrial dysfunction and high lethality upon sepsis.

• Inflammation
• Liver failure
• Mitochondria
• Reactive oxygen species
• Signaling

Aristolochia manshuriensis Kom (AMK) is an herb used as a traditional medicine; however, it causes side effects such as nephrotoxicity and carcinogenicity. Nevertheless, AMK can be applied in specific ways medicinally, including via ingestion of low doses for short periods of time. Non-alcoholic steatohepatitis (NASH) induced the hepatocyte injury and inflammation. The protective effects of AMK against NASH are unclear; therefore, in this study, the protective effects of AMK ethyl acetate extract were investigated in a high-fat diet (HFD)-induced NASH model. We found decreased hepatic steatosis and inflammation, as well as increased levels of lipoproteins during AMK extract treatment. We also observed decreased hepatic lipid peroxidation and triglycerides, as well as suppressed hepatic expression of lipogenic genes in extract-treated livers. Treatment with extract decreased the activation of c-jun N-terminal kinase 1/2 (JNK1/2) and increased the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). These results demonstrate that the protective effect of the extract against HFD-induced NASH occurred via reductions in reactive oxygen species production, inflammation suppression, and apoptosis related to the suppression of JNK1/2 activation and increased ERK1/2 phosphorylation. Taken together, these results indicate that that ethyl acetate extract of AMK has potential therapeutic effects in the HFD-induced NASH mouse model.

• Aristolochia manshuriensis Kom
• c-jun N-terminal kinase 1/2
• extracellular signal-regulated kinase 1/2
• inflammation
• nonalcoholic steatohepatitis

• Apoptosis
• Bax
• Caspase
• NGF
• Reactive oxygen
• Sympathetic neuron

• Akt
• apoptosis
• liver
• sepsis
• tumor necrosis factor

• inflammation
• insulin resistance
• liver
• type 2 diabetes mellitus
• vitamin D

• Inflammation
• Mouse Model
• Obesity
• Stress Signaling

• Animals
• Biomarkers/metabolism
• Biopsy
• Diet/methods
• Disease Models, Animal
• Fatty Liver/chemically induced
• Fatty Liver/drug therapy
• Fatty Liver/genetics
• Fatty Liver/metabolism
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Humans
• Insulin Resistance
• Lipid Peroxidation/drug effects
• Liver/cytology
• Liver/pathology
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/pathology
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NADP/administration & dosage
• NADP/pharmacology
• NADPH Oxidase 4
• NADPH Oxidases/metabolism
• Obesity/drug therapy
• Obesity/metabolism
• Oxidative Stress/drug effects
• Protein Phosphatase 1/metabolism
• Pyrazoles/metabolism
• Pyrazolones
• Pyridines/metabolism
• Pyridones
• Stress, Physiological/drug effects

• K01 DK090121 NIDDK NIH HHS
• U24 DK092993 NIDDK NIH HHS
• DK095359 NIDDK NIH HHS
• I01 BX002418 BLRD VA
• U24 DK059635 NIDDK NIH HHS
• R01 DK083283 NIDDK NIH HHS
• R01 DK090492 NIDDK NIH HHS
• DK083283 NIDDK NIH HHS
• R00 DK100736 NIDDK NIH HHS
• DK059635 NIDDK NIH HHS
• R01 DK095359 NIDDK NIH HHS
• R56 DK083283 NIDDK NIH HHS

• Fatty liver
• antioxidant
• carotenoid
• non-alcoholic steatohepatitis
• oxidative stress
• steatosis

• Non-alcoholic fatty liver disease
• non-alcoholic steatohepatitis
• obesity
• paediatric

• Administration, Oral
• Animals
• Apoptosis
• Autophagy/drug effects
• Cells, Cultured
• Concanavalin A/administration & dosage
• Concanavalin A/toxicity
• Cytokines/metabolism
• Drug Administration Schedule
• Hepatitis, Autoimmune/enzymology
• Hepatitis, Autoimmune/immunology
• Hepatitis, Autoimmune/prevention & control
• Hepatocytes/drug effects
• Liver/cytology
• Liver/drug effects
• Liver/enzymology
• Liver/pathology
• MAP Kinase Signaling System/drug effects
• Mice
• Mice, Inbred BALB C
• Xanthophylls/administration & dosage
• Xanthophylls/pharmacology

Autophagy is a lysosomal degradative pathway that plays an important role in maintaining cellular homeostasis. We previously showed that the inhibition of autophagy causes pancreatic β-cell apoptosis, suggesting that autophagy is a protective mechanism for the survival of pancreatic β-cells. The current study demonstrates that treatment with inhibitors and knockdown of the lysosomal cysteine proteases such as cathepsins B and L impair autophagy, enhancing the caspase-dependent apoptosis of INS-1 cells and islets upon exposure to high concentration of glucose. Interestingly, treatment with cathepsin B and L inhibitors prevented the proteolytic processing of cathepsins B, D and L, as evidenced by gradual accumulation of the respective pro-forms. Of note, inhibition of aspartic cathepsins had no effect on autophagy and cell viability, suggesting the selective role of cathepsins B and L in the regulation of β-cell autophagy and apoptosis. Lysosomal localization of accumulated pro-cathepsins in the presence of cathepsin B and L inhibitors was verified via immunocytochemistry and lysosomal fractionation. Lysotracker staining indicated that cathepsin B and L inhibitors led to the formation of severely enlarged lysosomes in a time-dependent manner. The abnormal accumulation of pro-cathepsins following treatment with inhibitors of cathepsins B and L suppressed normal lysosomal degradation and the processing of lysosomal enzymes, leading to lysosomal dysfunction. Collectively, our findings suggest that cathepsin defects following the inhibition of cathepsin B and L result in lysosomal dysfunction and consequent cell death in pancreatic β-cells.

• Apoptosis
• HCC
• IKKγ/NEMO
• Jnk1
• Jnk2
• Necrosis

AIM: To analyze the role of CYLD for receptor-mediated cell death of murine hepatocytes in acute liver injury models.

METHODS: Hepatocyte cell death in CYLD knockout mice (CYLD^-/-) was analyzed by application of liver injury models for CD95- (Jo2) and tumor necrosis factor (TNF)-α- [D-GalN/lipopolysaccharide (LPS)] induced apoptosis. Liver injury was assessed by measurement of serum transaminases and histological analysis. Apoptosis induction was quantified by cleaved PARP staining and Western blotting of activated caspases. Nuclear factor (NF)-κB, ERK, Akt and jun amino-terminal kinases signaling were assessed. Primary Hepatocytes were isolated by two step-collagenase perfusion and treated with recombinant TNF-α and with the CD95-ligand Jo2. Cell viability was analyzed by MTT-assay.

RESULTS: Livers of CYLD^-/- mice showed increased anti-apoptotic NF-κB signaling. In both applied liver injury models CYLD^-/- mice showed a significantly reduced apoptosis sensitivity. After D-GalN/LPS treatment CYLD^-/- mice exhibited significantly lower levels of alanine aminotransferase (ALT) (295 U/L vs 859 U/L, P < 0.05) and aspartate aminotransferase (AST) (560 U/L vs 1025 U/L, P < 0.01). After Jo injection CYLD^-/- mice showed 2-fold lower ALT (50 U/L vs 110 U/L, P < 0.01) and lower AST (250 U/L vs 435 U/L, P < 0.01) serum-levels compared to WT mice. In addition, isolated CYLD^-/- primary murine hepatocytes (PMH) were less sensitive towards death receptor-mediated apoptosis and showed increased levels of Bcl-2, XIAP, cIAP1/2, survivin and c-FLIP expression upon TNF- and CD95-receptor triggering, respectively. Inhibition of NF-κB activation by the inhibitor of NF-κB phosphorylation inhibitor BAY 11-7085 inhibited the expression of anti-apoptotic proteins and re-sensitized CYLD^-/- PMH towards TNF- and CD95-receptor mediated cell death.

CONCLUSION: CYLD is a central regulator of apoptotic cell death in murine hepatocytes by controlling NF-κB dependent anti-apoptotic signaling.

• CYLD
• Apoptosis
• Nuclear factor-κB
• Tumor necrosis factor-α
• CD95
• Liver

• Animals
• Antibodies
• Apoptosis/drug effects
• Biomarkers/blood
• Cell Survival
• Cells, Cultured
• Chemical and Drug Induced Liver Injury/enzymology
• Chemical and Drug Induced Liver Injury/etiology
• Chemical and Drug Induced Liver Injury/genetics
• Chemical and Drug Induced Liver Injury/immunology
• Chemical and Drug Induced Liver Injury/pathology
• Chemical and Drug Induced Liver Injury/prevention & control
• Cysteine Endopeptidases/deficiency
• Cysteine Endopeptidases/genetics
• Deubiquitinating Enzyme CYLD
• Disease Models, Animal
• Galactosamine
• Gene Deletion
• Hepatocytes/drug effects
• Hepatocytes/enzymology
• Hepatocytes/immunology
• Hepatocytes/pathology
• Lipopolysaccharides
• Mice, Knockout
• NF-kappa B/antagonists & inhibitors
• NF-kappa B/metabolism
• Receptors, Tumor Necrosis Factor/metabolism
• Signal Transduction/drug effects
• Time Factors
• Tumor Necrosis Factor-alpha/metabolism
• fas Receptor/immunology
• fas Receptor/metabolism

Non-alcoholic fatty liver disease affects approximately one-third of the population worldwide, and its incidence continues to increase with the increasing prevalence of other metabolic disorders such as type 2 diabetes. As non-alcoholic fatty liver disease can progress to liver cirrhosis, its treatment is attracting greater attention. The pathogenesis of non-alcoholic fatty liver disease is closely associated with insulin resistance and dyslipidemia, especially hypertriglyceridemia. Increased serum levels of free fatty acid and glucose can cause oxidative stress in the liver and peripheral tissue, leading to ectopic fat accumulation, especially in the liver. In this review, we summarize the mechanism underlying the progression of hepatic steatosis to steatohepatitis and cirrhosis. We also discuss established drugs that are already being used to treat non-alcoholic fatty liver disease, in addition to newly discovered agents, with respect to their mechanisms of drug action, focusing mainly on hepatic insulin resistance. As well, we review clinical data that demonstrate the efficacy of these drugs, together with improvements in biochemical or histological parameters.

• Non-alcoholic fatty liver disease
• Insulin resistance
• Drugs
• Pathogenesis

Stathmin 1 performs a critical function in cell proliferation by regulating microtubule polymerization. This proliferative function is thought to explain the frequent overexpression of stathmin in human cancer and its correlation with a bad prognosis. Whether stathmin also functions in cell death pathways is unclear. Stathmin regulates microtubules in part by binding free tubulin, a process inhibited by stathmin phosphorylation from kinases including c-Jun N-terminal kinase (JNK). The involvement of JNK activation both in stathmin phosphorylation, and in hepatocellular resistance to oxidative stress, led to an examination of the role of stathmin/JNK crosstalk in oxidant-induced hepatocyte death. Oxidative stress from menadione-generated superoxide induced JNK-dependent stathmin phosphorylation at Ser-16, Ser-25 and Ser-38 in hepatocytes. A stathmin knockdown sensitized hepatocytes to both apoptotic and necrotic cell death from menadione without altering levels of oxidant generation. The absence of stathmin during oxidative stress led to JNK overactivation that was the mechanism of cell death as a concomitant knockdown of JNK1 or JNK2 blocked death. Hepatocyte death from JNK overactivation was mediated by the effects of JNK on mitochondria. Mitochondrial outer membrane permeabilization occurred in stathmin knockdown cells at low concentrations of menadione that triggered apoptosis, whereas mitochondrial β-oxidation and ATP homeostasis were compromised at higher, necrotic menadione concentrations. Stathmin therefore mediates hepatocyte resistance to death from oxidative stress by down regulating JNK and maintaining mitochondrial integrity. These findings demonstrate a new mechanism by which stathmin promotes cell survival and potentially tumor growth.

• Animals
• Apoptosis/drug effects
• Cell Line
• Down-Regulation/drug effects
• Gene Knockdown Techniques
• HEK293 Cells
• Hepatocytes/cytology
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Humans
• Mitochondria/drug effects
• Mitochondria/metabolism
• Mitogen-Activated Protein Kinase 8/deficiency
• Mitogen-Activated Protein Kinase 8/genetics
• Mitogen-Activated Protein Kinase 8/metabolism
• Mitogen-Activated Protein Kinase 9/deficiency
• Mitogen-Activated Protein Kinase 9/genetics
• Mitogen-Activated Protein Kinase 9/metabolism
• Necrosis/chemically induced
• Oxidative Stress/drug effects
• Rats
• Signal Transduction/drug effects
• Stathmin/deficiency
• Stathmin/genetics
• Stathmin/metabolism
• Vitamin K 3/pharmacology

• R01 DK044234 NIDDK NIH HHS
• R01DK044234 NIDDK NIH HHS

• Alcoholic Liver Disease
• Apoptosis
• Caspases
• Clinical Trial
• DAMP
• DILI
• Hepatocellular Carcinoma
• NASH
• Necroptosis
• Necrosis
• Necrosome
• RIP Kinases
• RIP3
• Viral Hepatitis

• Inflammation
• Monoclonal antibody
• Neuropathology
• Tumor necrosis factor
• Tumor necrosis factor receptor

• Chemoprevention
• Dietary natural compounds
• Nonalcoholic fatty liver disease

• Allografts
• Animals
• Cell Death/drug effects
• Cytoprotection/drug effects
• Enzyme Inhibitors/pharmacology
• Enzyme Inhibitors/therapeutic use
• Graft Rejection/drug therapy
• Graft Rejection/pathology
• Graft Rejection/prevention & control
• Immunosuppressive Agents/pharmacology
• Immunosuppressive Agents/therapeutic use
• Kidney/drug effects
• Kidney/pathology
• Kidney Transplantation/adverse effects
• Male
• NF-kappa B/metabolism
• Phosphatidylinositol 3-Kinases/metabolism
• Poly(ADP-ribose) Polymerase Inhibitors
• Proto-Oncogene Proteins c-akt/metabolism
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Rats
• Signal Transduction/drug effects

• Apoptosis
• Caspases
• Hepatocarcinoma
• JNK
• TNF

FUZHENGHUAYU Tablets have been widely used in the treatment of liver fibrosis in China. Here, we investigate the apoptotic effect of FUZHENGHUAYU Tablet in rat liver stellate cell line HSC-T6. HSC-T6 cells were incubated with control serum or drug serum from rats fed with 0.9% NaCl or FUZHENGHUAYU Tablet, respectively. Cells exposed to drug serum showed higher proportions of early and late apoptotic cells than controls. The mRNA levels of collagens I and III, TGF-β1 and α-SMA were reduced by drug serum compared to control serum. Differentially expressed mRNAs and miRNAs were analyzed by microarray and sequencing, respectively. We identified 334 differentially expressed mRNAs and also 60 GOs and two pathways related to the mRNAs. Seventy-five differentially expressed miRNAs were down-regulated by drug serum and 1963 target genes were predicted. 134 GOs up-regulated in drug serum group were linked to miRNA targets, and drug serum also regulated 43 miRNA signal transduction pathways. Protein levels were evaluated by Western blot. Drug serum down-regulated (phospho-SAPK/JNK)/(SAPK/JNK) and up-regulated phospho-p38/p38 ratios. The study showed that FUZHENGHUAYU Tablet induced apoptosis in rat HSC-T6 cells possibly in part by activating p38 and inhibiting SAPK/JNK.

• p38 mapk
• c-jun nh₂-terminal kinase
• hepatocytes
• nonparenchymal cells
• cytokines

• Alanine Transaminase/blood
• Animals
• Apoptosis/drug effects
• Benzamides
• Cell Movement/drug effects
• Cells, Cultured
• Chemokine CCL2/metabolism
• Chemokine CXCL2/metabolism
• Enzyme Activation/drug effects
• Hepatocytes
• Imatinib Mesylate
• Interleukin-1beta/metabolism
• Interleukin-6/metabolism
• MAP Kinase Signaling System/drug effects
• Male
• Mice
• Mice, Inbred C57BL
• Monocytes/physiology
• Phosphorylation/drug effects
• Piperazines/therapeutic use
• Protein Kinase Inhibitors/therapeutic use
• Proto-Oncogene Proteins c-abl/metabolism
• Proto-Oncogene Proteins c-kit/metabolism
• Pyrimidines/pharmacology
• Pyrimidines/therapeutic use
• Receptor, Macrophage Colony-Stimulating Factor/metabolism
• Receptor, Platelet-Derived Growth Factor alpha/metabolism
• Receptor, Platelet-Derived Growth Factor beta/metabolism
• Reperfusion Injury/metabolism
• Reperfusion Injury/pathology
• Reperfusion Injury/prevention & control

• R01 DK068346 NIDDK NIH HHS
• T32 CA009501 NCI NIH HHS
• DK068346 NIDDK NIH HHS

• apoptosis
• atp
• fatty acid oxidation
• menadione
• necrosis

• Adenosine Triphosphate/metabolism
• Adenoviridae/genetics
• Adenoviridae/metabolism
• Animals
• Anthracenes/pharmacology
• Cell Death
• Cell Line, Transformed
• Drug Resistance
• Gene Knockdown Techniques
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Hepatocytes/pathology
• MAP Kinase Signaling System
• Mice
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinase 9/antagonists & inhibitors
• Mitogen-Activated Protein Kinase 9/genetics
• Mitogen-Activated Protein Kinase 9/metabolism
• Oleic Acid/pharmacology
• Oxidation-Reduction
• Oxidative Stress
• Peptide Fragments/genetics
• Peptide Fragments/metabolism
• Phosphorylation
• Proto-Oncogene Proteins c-jun/genetics
• Proto-Oncogene Proteins c-jun/metabolism
• RNA, Small Interfering/genetics
• RNA, Small Interfering/metabolism
• Rats
• Reactive Oxygen Species/metabolism
• Vitamin K 3/toxicity

• R01 DK044234 NIDDK NIH HHS
• R56 DK044234 NIDDK NIH HHS
• DK007218 NIDDK NIH HHS
• T32 DK007218 NIDDK NIH HHS
• DK044234 NIDDK NIH HHS

• mapk
• hepatocellular carcinoma
• insulin resistance
• c-jun
• tnf
• acetaminophen

Hemorrhagic shock leads to hepatic hypoperfusion and activation of mitogen-activated stress kinases (MAPK) like c-Jun N-terminal kinase (JNK) 1 and 2. Our aim was to determine whether mitochondrial dysfunction leading to hepatic necrosis and apoptosis after hemorrhage/resuscitation (H/R) was dependent on JNK2. Under pentobarbital anesthesia, wildtype (WT) and JNK2 deficient (KO) mice were hemorrhaged to 30 mm Hg for 3 h and then resuscitated with shed blood plus half the volume of lactated Ringer's solution. Serum alanine aminotransferase (ALT), necrosis, apoptosis and oxidative stress were assessed 6 h after resuscitation. Mitochondrial polarization was assessed by intravital microscopy. After H/R, ALT in WT-mice increased from 130 U/L to 4800 U/L. In KO-mice, ALT after H/R was blunted to 1800 U/l (P < 0.05). Necrosis, caspase-3 activity and ROS were all substantially decreased in KO compared to WT mice after H/R. After sham operation, intravital microscopy revealed punctate mitochondrial staining by rhodamine 123 (Rh123), indicating normal mitochondrial polarization. At 4 h after H/R, Rh123 staining became dim and diffuse in 58% of hepatocytes, indicating depolarization and onset of the mitochondrial permeability transition (MPT). By contrast, KO mice displayed less depolarization after H/R (23%, P < 0.05). In conclusion, JNK2 contributes to MPT-mediated liver injury after H/R.

• adenosine
• apoptosis
• cancer therapy
• fructose
• jun n-terminal kinase (jnk)
• tumor necrosis factor (tnf)
• cd95

• Adenosine Triphosphate/metabolism
• Animals
• Apoptosis/drug effects
• Cells, Cultured
• Cyclic AMP/metabolism
• Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors
• Cyclic AMP-Dependent Protein Kinases/metabolism
• Fructose/pharmacology
• Hepatocytes
• MAP Kinase Kinase 4/metabolism
• MAP Kinase Signaling System/drug effects
• Mice
• Sweetening Agents/pharmacology
• Tumor Necrosis Factor-alpha/pharmacology
• fas Receptor/metabolism

• Animals
• Anthracenes/pharmacology
• Apoptosis
• CASP8 and FADD-Like Apoptosis Regulating Protein/deficiency
• CASP8 and FADD-Like Apoptosis Regulating Protein/genetics
• Caspases/metabolism
• Chemical and Drug Induced Liver Injury/metabolism
• Chemical and Drug Induced Liver Injury/pathology
• Concanavalin A/toxicity
• Female
• Galactosamine/toxicity
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Hepatocytes/pathology
• Lipopolysaccharides/toxicity
• MAP Kinase Signaling System/drug effects
• Mice
• Mice, Knockout
• Receptors, Death Domain/metabolism
• fas Receptor/agonists

• non-alcoholic steatohepatitis
• non-alcoholic fatty liver disease
• diabetes
• endoplasmic reticulum
• methionine choline deficient diet

• Activating Transcription Factor 6/metabolism
• Animal Feed
• Animals
• Choline/pharmacology
• Choline Deficiency/metabolism
• Cytokines/metabolism
• Diabetes Mellitus, Experimental/metabolism
• Eukaryotic Initiation Factor-2/metabolism
• Fatty Liver/metabolism
• Female
• JNK Mitogen-Activated Protein Kinases/metabolism
• Methionine/deficiency
• Methionine/pharmacology
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Non-alcoholic Fatty Liver Disease
• Obesity/metabolism
• Protein Phosphatase 1/metabolism
• Signal Transduction/physiology
• Transcription Factor CHOP/metabolism
• Unfolded Protein Response/physiology

• R01 DK080810 NIDDK NIH HHS
• R01 DK080810-02 NIDDK NIH HHS
• R01 DK080810 NIDDK NIH HHS
• K08 DK066032-04 NIDDK NIH HHS
• K08 DK066032 NIDDK NIH HHS

• cytochrome p450 2e1
• c-jun n-terminal kinase
• oxidative stress
• liver injury
• mitochondrial damage

• Alanine Transaminase/blood
• Animals
• Caspase 3/metabolism
• Caspase 8/metabolism
• Catalase/metabolism
• Chemical and Drug Induced Liver Injury/epidemiology
• Chemical and Drug Induced Liver Injury/genetics
• Chemical and Drug Induced Liver Injury/metabolism
• Enzyme Inhibitors/toxicity
• Female
• Lipid Peroxidation/physiology
• Liver Diseases, Alcoholic/epidemiology
• Liver Diseases, Alcoholic/genetics
• Liver Diseases, Alcoholic/metabolism
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondria/metabolism
• Mitogen-Activated Protein Kinase 8/genetics
• Mitogen-Activated Protein Kinase 8/metabolism
• Mitogen-Activated Protein Kinase 9/genetics
• Mitogen-Activated Protein Kinase 9/metabolism
• Nitric Oxide Synthase Type II/metabolism
• Oxidative Stress/physiology
• Pyrazoles/toxicity
• Risk Factors
• Tumor Necrosis Factor-alpha/toxicity

• R01 AA017425-02 NIAAA NIH HHS
• R01 AA017425 NIAAA NIH HHS
• R01 AA003312-25 NIAAA NIH HHS
• R01 AA018790 NIAAA NIH HHS
• R01 AA018790-02 NIAAA NIH HHS

Chemo-resistance to cisplatin-centered cancer therapy is a major obstacle to the effective treatment of human ovarian cancer. Previous reports indicated that arsenic trioxide (ATO) induces cell apoptosis in both drug-sensitive and -resistant ovarian cancer cells.

In this study, we determined the molecular mechanism of ATO-induced apoptosis in ovarian cancer cells. Our data demonstrated that ATO induced cell apoptosis by decreasing levels of phosphorylated AKT (p-AKT) and activating caspase-3 and caspase-9. Importantly, BIM played a critical role in ATO-induced apoptosis. The inhibition of BIM expression prevented AKT dephosphorylation and inhibited caspase-3 activation during cell apoptosis. However, surprisingly, gene silencing of AKT or FOXO3A had little effect on BIM expression and phosphorylation. Moreover, the activation of caspase-3 by ATO treatment improved AKT dephosphorylation, not only by cleaving the regulatory A subunit of protein phosphatase 2A (PP2A), but also by increasing its activation. Furthermore, our data indicated that the c-Jun N-terminal kinases (JNK) pathway is involved in the regulation of BIM expression.

We demonstrated the roles of BIM in ATO-induced apoptosis and the molecular mechanisms of BIM expression regulated by ATO during ovarian cancer cell apoptosis. Our findings suggest that BIM plays an important role in regulating p-AKT by activating caspase-3 and that BIM mediates the level of AKT phosphorylation to determine the threshold for overcoming cisplatin resistance in ovarian cancer cells.

• Apoptosis/drug effects
• Apoptosis Regulatory Proteins/genetics
• Apoptosis Regulatory Proteins/metabolism
• Arsenic Trioxide
• Arsenicals/pharmacology
• Bcl-2-Like Protein 11
• Cell Line, Tumor
• Cell Survival/drug effects
• Cisplatin/pharmacology
• Electrophoresis, Polyacrylamide Gel
• Female
• Forkhead Box Protein O3
• Forkhead Transcription Factors/genetics
• Forkhead Transcription Factors/metabolism
• Gene Silencing
• Humans
• Immunoblotting
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Ovarian Neoplasms/metabolism
• Oxides/pharmacology
• Phosphorylation/drug effects
• Proto-Oncogene Proteins/genetics
• Proto-Oncogene Proteins/metabolism
• Proto-Oncogene Proteins c-akt/genetics
• Proto-Oncogene Proteins c-akt/metabolism
• RNA, Small Interfering