Role of gut microbiota and oxidative stress in the progression of non-alcoholic fatty liver disease to hepatocarcinoma: Current and innovative therapeutic approaches

A peculiar role for oxidative stress in non-alcoholic fatty liver disease (NAFLD) and its transition to the inflammatory complication non-alcoholic steatohepatitis (NASH), as well as in its threatening evolution to hepatocellular carcinoma (HCC), is supported by numerous experimental and clinical studies. NADPH oxidases (NOXs) are enzymes producing reactive oxygen species (ROS), whose abundance in liver cells is closely related to inflammation and immune responses. Here, we reviewed recent findings regarding this topic, focusing on the role of NOXs in the different stages of fatty liver disease and describing the current knowledge about their mechanisms of action. We conclude that, although there is a consensus that NOX-produced ROS are toxic in non-neoplastic conditions due to their role in the inflammatory vicious cycle sustaining the transition of NAFLD to NASH, their effect is controversial in the neoplastic transition towards HCC. In this regard, there are indications of a differential effect of NOX isoforms, since NOX1 and NOX2 play a detrimental role, whereas increased NOX4 expression appears to be correlated with better HCC prognosis in some studies. Further studies are needed to fully unravel the mechanisms of action of NOXs and their relationships with the signaling pathways modulating steatosis and liver cancer development.

Download Full-text

Addressing the liver progenitor cell response and hepatic oxidative stress in experimental non-alcoholic fatty liver disease/non-alcoholic steatohepatitis using amniotic epithelial cells

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02476-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Mihiri Goonetilleke ◽

Nathan Kuk ◽

Jeanne Correia ◽

Alex Hodge ◽

Gregory Moore ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Disease ◽

Epithelial Cells ◽

Fatty Liver ◽

Progenitor Cells ◽

Fatty Liver Disease ◽

Hepatic Inflammation ◽

Alcoholic Fatty Liver ◽

And Oxidative Stress ◽

Alcoholic Fatty Liver Disease

Abstract Background Non-alcoholic fatty liver disease is the most common liver disease globally and in its inflammatory form, non-alcoholic steatohepatitis (NASH), can progress to cirrhosis and hepatocellular carcinoma (HCC). Currently, patient education and lifestyle changes are the major tools to prevent the continued progression of NASH. Emerging therapies in NASH target known pathological processes involved in the progression of the disease including inflammation, fibrosis, oxidative stress and hepatocyte apoptosis. Human amniotic epithelial cells (hAECs) were previously shown to be beneficial in experimental models of chronic liver injury, reducing hepatic inflammation and fibrosis. Previous studies have shown that liver progenitor cells (LPCs) response plays a significant role in the development of fibrosis and HCC in mouse models of fatty liver disease. In this study, we examined the effect hAECs have on the LPC response and hepatic oxidative stress in an experimental model of NASH. Methods Experimental NASH was induced in C57BL/6 J male mice using a high-fat, high fructose diet for 42 weeks. Mice received either a single intraperitoneal injection of 2 × 106 hAECs at week 34 or an additional hAEC dose at week 38. Changes to the LPC response and oxidative stress regulators were measured. Results hAEC administration significantly reduced the expansion of LPCs and their mitogens, IL-6, IFNγ and TWEAK. hAEC administration also reduced neutrophil infiltration and myeloperoxidase production with a concurrent increase in heme oxygenase-1 production. These observations were accompanied by a significant increase in total levels of anti-fibrotic IFNβ in mice treated with a single dose of hAECs, which appeared to be independent of c-GAS-STING activation. Conclusions Expansion of liver progenitor cells, hepatic inflammation and oxidative stress associated with experimental NASH were attenuated by hAEC administration. Given that repeated doses did not significantly increase efficacy, future studies assessing the impact of dose escalation and/or timing of dose may provide insights into clinical translation.

Download Full-text

The crucial role of oxidative stress in non-alcoholic fatty liver disease-induced male reproductive toxicity: the ameliorative effects of Iranian indigenous probiotics

Naunyn-Schmiedeberg s Archives of Pharmacology ◽

10.1007/s00210-021-02177-0 ◽

2022 ◽

Author(s):

Mohammad Mehdi Ommati ◽

Huifeng Li ◽

Akram Jamshidzadeh ◽

Fereshteh Khoshghadam ◽

Socorro Retana-Márquez ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Disease ◽

Fatty Liver ◽

Crucial Role ◽

Fatty Liver Disease ◽

Reproductive Toxicity ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

Download Full-text

The Bisphenol A Induced Oxidative Stress in Non-Alcoholic Fatty Liver Disease Male Patients: A Clinical Strategy to Antagonize the Progression of the Disease

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17103369 ◽

2020 ◽

Vol 17 (10) ◽

pp. 3369 ◽

Cited By ~ 1

Author(s):

Alessandro Federico ◽

Marcello Dallio ◽

Antonietta Gerarda Gravina ◽

Nadia Diano ◽

Sonia Errico ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Disease ◽

Bisphenol A ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Free Form ◽

Alcoholic Fatty Liver ◽

Male Patients ◽

And Oxidative Stress ◽

Alcoholic Fatty Liver Disease

Introduction: Bisphenol A (BPA) exposure has been correlated to non-alcoholic fatty liver disease (NAFLD) development and progression. We investigated, in a clinical model, the effects of the administration of 303 mg of silybin phospholipids complex, 10 μg of vitamin D, and 15 mg of vitamin E (RealSIL, 100D, IBI-Lorenzini, Aprilia, Italy) in male NAFLD patients exposed to BPA on metabolic, hormonal, and oxidative stress-related parameters. Methods: We enrolled 32 male patients with histologic diagnosis of NAFLD and treated them with Realsil 100D twice a day for six months. We performed at baseline clinical, biochemical, and food consumption assessments as well as the evaluation of physical exercise, thiobarbituric acid reactive substances (TBARS), plasmatic and urinary BPA and estrogen levels. The results obtained were compared with those of healthy control subjects and, in the NAFLD group, between baseline and the end of treatment. Results: A direct proportionality between TBARS levels and BPA exposure was shown (p < 0.0001). The therapy determined a reduction of TBARS levels (p = 0.011), an improvement of alanine aminotransferase, aspartate aminotransferase, insulinemia, homeostatic model assessment insulin resistance, C reactive protein, tumor necrosis factor alpha (p < 0.05), an increase of conjugated BPA urine amount, and a reduction of its free form (p < 0.0001; p = 0.0002). Moreover, the therapy caused an increase of plasmatic levels of the native form of estrogens (p = 0.03). Conclusions: We highlighted the potential role of BPA in estrogen oxidation and oxidative stress in NAFLD patients. The use of Realsil 100D could contribute to fast BPA detoxification and to improve cellular antioxidant power, defending the integrity of biological estrogen-dependent pathways.

Download Full-text