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

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 dosedependently 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.