PPARγ attenuates hepatic inflammation and oxidative stress of non‑alcoholic steatohepatitis via modulating the miR‑21‑5p/SFRP5 pathway

Abstract Background: Non-alcoholic steatohepatitis (NASH) is the most common liver disease globally and can progress to cirrhosis and hepatocellular carcinoma (HCC). Currently, patient education and lifestyle changes are the major tools to prevent the continuous progression of NASH. Emerging therapies in NASH target known pathological processes involved in the progression of the disease including inflammation, fibrosis, oxidative stress and 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 the interaction between liver progenitor cells (LPCs) 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/6J 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 IFNb 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.

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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.

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Are N-acetylcysteine and adalimumab effective for non-alcoholic steatohepatitis?

Gastroenterology Insights ◽

10.4081/gi.2016.6227 ◽

2016 ◽

Vol 7 (1) ◽

Author(s):

Mustafa Yalçın ◽

Muhammed Ali Kıyak ◽

Mesut Akarsu ◽

Aslı Çelik ◽

Göksel Bengi ◽

...

Keyword(s):

Oxidative Stress ◽

Treatment Options ◽

Diet Group ◽

Normal Diet ◽

The Other ◽

Albino Rats ◽

Necrosis Factor Alpha ◽

Alcoholic Steatohepatitis ◽

Tnf Α ◽

And Oxidative Stress

Due to the lack of effective medical treatment for non-alcoholic steatohepatitis (NASH), we aimed to evaluate new treatment options. In particular, our goal was to investigate and compare the effects of N-acetylcysteine (NAC) and Adalimumab treatment on tumor necrosis factor alpha (TNF-α) and oxidative stress during the development of NASH in a rat model of the disease. Our study included a total of 35 female Wistar albino rats that were divided into 5 groups of 7 each, and evaluated over a 6 week period. One group received a normal diet, while the other four groups received a methionine and choline deficient (MCD) diet. One of the groups receiving the MCD diet did not take any medicine, while the other three were administered NAC, adalimumab, or a NAC/adalimumab combination therapy. NASH was successfully established in the MCD diet group. Levels of TNF-α were effectively suppressed in the three groups that received therapy. Even though adalimumab significantly enhanced suppression of TNF-α, the NASH score was suppressed to a more statistically significant extent in the groups receiving NAC. Our study showed that TNF-α and oxidative stress play an important role in NASH pathogenesis. The antioxidant agent, NAC, was found to be superior to the anti-TNF agent, Adalimumab, in the improvement of total NASH score. Although these drugs did not prevent the development of NASH, it was shown that they mildly reverse the NASH histopathology score, suggesting improvement of and overall liver function.

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Silibinin ameliorates hepatic lipid accumulation and oxidative stress in mice with non-alcoholic steatohepatitis by regulating CFLAR-JNK pathway

Acta Pharmaceutica Sinica B ◽

10.1016/j.apsb.2019.02.006 ◽

2019 ◽

Vol 9 (4) ◽

pp. 745-757 ◽

Cited By ~ 19

Author(s):

Yayun Liu ◽

Wei Xu ◽

Ting Zhai ◽

Jiaojiao You ◽

Yong Chen

Keyword(s):

Oxidative Stress ◽

Lipid Accumulation ◽

Jnk Pathway ◽

Hepatic Lipid ◽

Hepatic Lipid Accumulation ◽

Alcoholic Steatohepatitis ◽

And Oxidative Stress

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106 A role of resistin as a mediator of hepatic inflammation and oxidative stress

Journal of Hepatology ◽

10.1016/s0168-8278(06)80107-8 ◽

2006 ◽

Vol 44 ◽

pp. S46

Author(s):

C. Bertolani ◽

P. Sancho-Bru ◽

R. Bataller ◽

E. Zamara ◽

P. Failli ◽

...

Keyword(s):

Oxidative Stress ◽

Hepatic Inflammation ◽

And Oxidative Stress

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Necroptosis is a key pathogenic event in human and experimental murine models of non-alcoholic steatohepatitis

Clinical Science ◽

10.1042/cs20140732 ◽

2015 ◽

Vol 129 (8) ◽

pp. 721-739 ◽

Cited By ~ 85

Author(s):

Marta B. Afonso ◽

Pedro M. Rodrigues ◽

Tânia Carvalho ◽

Marta Caridade ◽

Paula Borralho ◽

...

Keyword(s):

Oxidative Stress ◽

Hepatic Steatosis ◽

Murine Models ◽

Alcoholic Steatohepatitis ◽

Regulated Necrosis ◽

Tnf Α ◽

And Oxidative Stress

Focusing on regulated necrosis in the liver, this study demonstrates that necroptosis contributes to NAFLD pathogenesis in humans and in experimental murine models of hepatic steatosis and NASH. Further, it establishes the involvement of TNF-α and oxidative stress in necroptotic signalling in hepatocytes.

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