Diacerein ameliorates acetaminophen hepatotoxicity in rats via inhibiting HMGB1/TLR4/NF-κB and upregulating PPAR-γ signal

Abstract

Background Acetaminophen (APAP) is a worldwide antipyretic as well as an analgesic medication. It has been extensively utilized during the outbreak of coronavirus 2019 (COVID-19). APAP misuse would lead to liver injury. Diacerein (DIA), an anthraquinone derivative, has antioxidant and inflammatory properties. Hence, this study attempted to evaluate the impact of DIA treatment on liver injury induced by APAP and its influence on nuclear factor-κB (NF-κB) /toll-like receptor 4 (TLR4)/high mobility group box-1(HMGB-1) signaling as well as the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) expression. Methods Male albino rats received 25 as well as 50 mg/kg/day DIA orally for seven days. One hour after the last administration, rats received APAP (1gm/kg, orally). For histopathological analysis, liver tissues and blood were collected, immunohistochemical (IHC) assay, biochemical assay, as well as quantitative real-time polymerase chain reaction (qRT-PCR). Results DIA markedly reduced liver injury markers and ameliorated histopathological changes. Moreover, DIA dose-dependently alleviated oxidative stress status caused by APAP administration along with inflammatory markers, including the level of interleukin-1 beta (IL-1β), myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6). Furthermore, DIA downregulated protein levels as well as mRNA of HMGB-1, TLR4, NF-κB p65 expression, and enhanced PPAR-γ expression. Moreover, DIA ameliorated apoptotic (Bax) and caspase-3 expressions and increased the anti-apoptotic (Bcl2) expression. Conclusions This study demonstrated that DIA exerts anti-apoptotic, anti-inflammatory, and antioxidant properties against liver injury induced by APAP that is attributed to inhibition of the HMGB1/TLR4/NF-κB pathway, besides upregulation of the expression of PPAR-γ.

Diacerein ameliorates cholestasis-induced liver fibrosis in rat via modulating HMGB1/RAGE/NF-κB/JNK pathway and endoplasmic reticulum stress

“…Our study revealed that diacerein reduced hepatic protein and gene expression of HMGB1 and gene expression of RAGE. These findings are in accordance with a recent study by Kamel et al 45 who proved that diacerein's hepatoprotective impact on acetaminophen-induced hepatotoxicity was brought about by inhibition of the HMGB1/TLR4 pathway.…”

Cardioprotective role of diacerein in diabetic cardiomyopathy via modulation of inflammasome/caspase1/interleukin1β pathway in juvenile rats

“…DIA could inhibit the process of synthesis and activity of various pro-inflammatory cytokines such as IL1β, TNF-α, NF-κB, and IL6 and therefore suppress inflammation, apoptosis, and fibrosis with its antioxidant effect causing elevation of the cardiac GSH and TAC associated with marked reduction of MDA content. These findings are compatible with several studies which reported that DIA counteracts ROS, and it has a powerful antioxidant capability in various body organs (El-Sherbiny et al, 2021 , Ding et al, 2022 , Mohamed Kamel et al, 2022 ). Prevention of inflammation and oxidative damage protects the cell wall and prevents leakage of the cardiac enzymes as there were significant decreases of cardiac enzymes in serum with normalization of the histopathological features.…”

Screening impacts of Tilmicosin induced-hepatic and renal toxicity in rats: Protection by Rhodiola Rosea extract through the involvement of oxidative stress, antioxidants, and inflammatory cytokines biomarkers

“…activates the innate immune system and the release of in ammatory mediators (TNF-α, NF k B, and IL-1β), causing severe hepatic and renal injuries [72]. Activation of HMGB1 binding receptors initiated the in ammatory responses [70,73].…”