Oxidative Stress Management in Chronic Liver Diseases and Hepatocellular Carcinoma

Uchida, Daisuke; Takaki, Akinobu; Oyama, Atsushi; Adachi, Takuya; Wada, Nozomu; Onishi, Hideki; Okada, Hiroyuki

doi:10.3390/nu12061576

Cited by 58 publications

(53 citation statements)

References 151 publications

(157 reference statements)

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“…Our results show that TGF-secretion by tumor cells could be in part responsible for activating stellate cells and for inducing the IRE1α-branch of the UPR. However, this seems to depend on the cell lines used, as the effect was not seen in the LX2 and (66,67). Therefore, an IRE1α-mediated regulation of ROS-generation might be a contributing factor that explains our findings on stellate cell activation and tumor cell proliferation after inhibiting IRE1α with 4μ8C or transfection.…”

Section: Discussionmentioning

confidence: 73%

“…In addition, ROS is one of the critical mediators of stellate cell activation and ECM-production ( Kong et al, 2019 ). Oxidative stress has been recognized as one of the key factors in the pathogenesis of HCC and treatment strategies aiming at controlling oxidative stress have shown promising pre-clinical results ( Takaki and Yamamoto, 2015 ; Uchida et al, 2020 ). Therefore, an IRE1α-mediated regulation of ROS-generation might be a contributing factor that explains our findings on stellate cell activation and tumor cell proliferation after inhibiting IRE1α with 4μ8C or transfection.…”

Section: Discussionmentioning

confidence: 99%

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Inhibiting IRE1α-endonuclease activity decreases tumor burden in a mouse model for hepatocellular carcinoma

Pavlović

Calitz

Thanapirom

et al. 2020

eLife

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Hepatocellular carcinoma (HCC) is a liver tumor that usually arises in patients with cirrhosis. Hepatic stellate cells are key players in the progression of HCC, as they create a fibrotic micro-environment and produce growth factors and cytokines that enhance tumor cell proliferation and migration. We assessed the role of endoplasmic reticulum (ER) stress in the cross-talk between stellate cells and HCC-cells. Mice with a fibrotic HCC were treated with the IRE1α-inhibitor 4μ8C, which reduced tumor burden and collagen deposition. By co-culturing HCC-cells with stellate cells, we found that HCC-cells activate IREα in stellate cells, thereby contributing to their activation. Inhibiting IRE1α blocked stellate cell activation, which then decreased proliferation and migration of tumor cells in different in vitro 2D and 3D co-cultures. In addition, we also observed cell-line specific direct effects of inhibiting IRE1α in tumor cells.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Inhibiting IRE1α-endonuclease activity decreases tumor burden in a mouse model for hepatocellular carcinoma

Pavlović

Calitz

Thanapirom

et al. 2020

eLife

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“…Liver fibrosis has been related to oxidative stress [ 26 , 27 ]. For this reason, we checked the MDA levels and the activity of antioxidant enzymes.…”

Section: Resultsmentioning

confidence: 99%

“…Oxidative stress has been recognized as a critical factor in the progression of many chronic liver diseases, including liver fibrosis [ 26 , 27 ]. ROS can disturb liver-specific cells’ functionality and, therefore, contribute to the development of liver fibrosis [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Long-Term Aspartame Administration Leads to Fibrosis, Inflammasome Activation, and Gluconeogenesis Impairment in the Liver of Mice

Finamor

Bressan

Torres-Cuevas

et al. 2021

Biology

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Background: Aspartame is an artificial sweetener used in foods and beverages worldwide. However, it is linked to oxidative stress, inflammation, and liver damage through mechanisms that are not fully elucidated yet. This work aimed to investigate the effects of long-term administration of aspartame on the oxidative and inflammatory mechanisms associated with liver fibrosis progression in mice. Methods: Mice were divided into two groups with six animals each: control and aspartame. Aspartame (80 mg/kg, via oral) or vehicle was administrated for 12 weeks. Results: Aspartame caused liver damage and elevated serum transaminase levels. Aspartame also generated liver fibrosis, as evidenced by histology analysis, and pro-fibrotic markers’ upregulation, including transforming growth factor β 1, collagen type I alpha 1, and alpha-smooth muscle actin. Furthermore, aspartame reduced nuclear factor erythroid 2-related factor 2 (Nrf2) activation and enzymatic antioxidant activity and increased lipid peroxidation, which triggered NOD-like receptor containing protein 3 (NLRP3) inflammasome activation and p53 induction. Furthermore, aspartame reduced peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) levels, possibly through p53 activation. This PGC-1α deficiency could be responsible for the changes in lipid profile in serum, total lipid accumulation, and gluconeogenesis impairment in liver, evidenced by the gluconeogenic enzymes’ downregulation, thus causing hypoglycemia. Conclusions: This work provides new insights to understand the mechanisms related to the adverse effects of aspartame on liver tissue.

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“…The cumulative production of ROS/RNS through either endogenous or exogenous insults is titled oxidative stress (OS) and is popular for numerous types of cancer cells that are connected with altered redox organization of cellular signaling paths. OS prompts a cellular redox imbalance that has been found to be present in different cancer cells as compared with normal cells; the redox imbalance thus may be linked to oncogenic inducement [7]. CCl 4 is an industrial chemical found in refrigerants and solvents for waxes, varnishes and other materials.…”

Section: Introductionmentioning

confidence: 99%

Curative Role of Dithiophenolato Titanium (IV)-Chitosan Nanocomposite Complex Against Carbon Tetrachloride-Induced Liver Injuries

Shaban¹,

Yehiaa²,

Awad³

et al. 2021

Preprint

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Background Titanium-based compounds have been incorporated as promising antineoplastic metals. In our previous studies, dithiophenolato titanium (IV) Complex "DBT" and its chitosan nanocomposite "DBT-CSNPs" were prepared and we showed that these compounds have antibacterial activities, cytotoxic, and have abilities to bind with DNA helixes. Therefore, in this study, we evaluated the LD50 values of dithiophenolato titanium (IV)-complex (DBT) and its high thermal stable chitosan nanoparticles (DBT-CSNPs). Then their therapeutic effects against liver injuries induced by carbon tetrachloride (CCl4) were assessed and compared with cisplatin treatment. Additionally, the anti-proliferative activity of DBT and DBT-CSNPs against human liver cancer (HepG2) cell lines through the analysis of the cell cycle was evaluated. Methods Nine groups of rats were prepared: normal, DBT, DBT-CSNPs, CSNPs, CCl4, CCl4-DBT, CCl4-DBT-CSNPs, CCl4-CSNPs and CCl4-cisplatin. Liver histopathology and the biochemical markers involving oxidative stress, apoptosis, liver and kidney functions, and lipid profile were determined. Results The results revealed that the treatment with DBT-CSNPs and DBT after CCl4 administration abolished liver damage since it reduced the apoptosis induced by CCl4 via the reduction of DNA fragmentation, Bax and caspase- 8 with an elevation of Bcl2 and Bcl2/Bax ratio. Also, these treatments caused nonsignificant changes in the markers of oxidative stress. Therefore, liver histopathology and functions, lipid profile, and kidney functions were improved. Cisplatin treatment reduced liver injury with a degree less than DBT-CSNPs and DBT, but it induced nephrotoxicity. Administration of DBT-CSNPs and DBT to healthy rats for 14 days has no adverse effect. Also, the results showed that DBT-CSNPs and DBT inhibited the proliferation of HepG2 cells by arresting cells in the G2/M phase and inducing cell death. Conclusion DBT-CSNPs and DBT have a therapeutic effect against CCl4-induced liver injuries via the reduction of apoptosis induced by CCl4. Moreover, both compounds have antineoplastic activities against the HepG2 cell line. In all cases, DBT-CSNPs have a greater effect due to their nanostructure. Therefore, both compounds can be used in the pharmacological fields, particularly DBT-CSNPs.

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Oxidative Stress Management in Chronic Liver Diseases and Hepatocellular Carcinoma

Cited by 58 publications

References 151 publications

Inhibiting IRE1α-endonuclease activity decreases tumor burden in a mouse model for hepatocellular carcinoma

Inhibiting IRE1α-endonuclease activity decreases tumor burden in a mouse model for hepatocellular carcinoma

Long-Term Aspartame Administration Leads to Fibrosis, Inflammasome Activation, and Gluconeogenesis Impairment in the Liver of Mice

Curative Role of Dithiophenolato Titanium (IV)-Chitosan Nanocomposite Complex Against Carbon Tetrachloride-Induced Liver Injuries

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