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Hepatocellular carcinoma (HCC) accounts for more than 5% of all human cancers. Diacerein (DIA), an interleukin (IL)-1β inhibitor, is used for the treatment of osteoarthritis. DIA is a potential anticancer drug acting on several protein targets in the process of apoptosis. The present study aimed to explore the molecular mechanisms underlying the effect of DIA in the treatment of trichloroacetic acid (TCA)–induced pre-neoplastic changes in rats. Rats were allocated into 5 groups and treated for 4 weeks. Group 1: control; received vehicle, Group 2: TCA group; received TCA (1 g/kg, orally for 5 days). Group 3: DIA-treated group; received TCA +DIA (50 mg/kg/day, orally, for 4 weeks). Group 4: positive control group; received TCA (1 g/kg, orally, for 5 days) + 5-fluorouracil (5-FU) (75 mg/kg) intraperitoneally (i.p.), for 4 weeks as a standard anticancer drug. Group 5: received TCA (1 g/kg, orally for 5 days) + DIA (50 mg/kg/day, orally, for 4 weeks) + 5-FU (75 mg/kg, i.p., for 4 weeks). Serum liver enzymes, oxidative stress parameters, inflammatory parameter (IL-1β), and angiogenesis marker vascular endothelial growth factor (VEGF) were assessed along with histopathological evaluation. An apoptotic marker as caspase-3 expression was measured by western blot analysis. Immunoexpression of proliferating cell nuclear antigen (PCNA) and hypoxia-inducible factor-1α (HIF-1α) was evaluated. Results and conclusion: The outcomes proved that at histological level, DIA ameliorated hepatic precancerous lesion via modulation of IL-1β–HIF-1α–VEGF pathway. Conclusion IL-1β mediates angiogenesis indirectly, as it has been shown to induce hypoxia-inducible factor-1α (HIF-1α) which upregulates VEGF.

Drug-induced cardiotoxicity is a serious adverse effect that occurs during the administration of chemotherapeutic agents such as cyclophosphamide (CYC). Therefore, there is a critical need to find cardioprotective agents to keep the heart healthy. The current study aimed to investigate the protective effect of simvastatin (SIM) against CYC-induced heart damage and evaluate different mechanisms involved in mediating this effect, including the inflammasome/caspase1/interleukin1β (IL1β) pathway and endothelial nitric oxide synthase (eNOS). 36 rats were randomly assigned to one of four groups: a control group that received only vehicles, a CYC group that received CYC (150 mg/kg/day) i.p. on the fourth and fifth days, a CYC+SIM group that received SIM (10 mg/kg/day) orally for 5 days and CYC (150 mg/kg/day) i.p. on the fourth and fifth days, and a CYC+SIM+ Nitro- ω-L-arginine (L-NNA) group that received L-NNA (25 mg/kg/day, SIM (10 mg/kg/day) orally for 5 days and CYC (150 mg/kg/day) i.p. on the 4th and 5th days. The CYC group revealed an obvious elevation in cardiac enzymes and heart weights with toxic histopathological changes. Moreover, there was an increase in malondialdehyde (MDA), tumor necrosis factor-alpha (TNFα) levels, and up-regulation of the NLRP3inflammasome/caspase1/IL1β pathway. In addition, total antioxidant capacity (TAC), eNOS, reduced glutathione (GSH), and superoxide dismutase (SOD) significantly decreased. CYC-induced cardiotoxicity was most properly reversed by SIM through its anti-oxidant, anti-inflammatory, and anti-apoptotic actions with the stimulation of eNOS. The co-administration of L-NNA diminished the protective effect of SIM, indicating the essential role of eNOS in mediating this effect. Therefore, SIM ameliorated CYC-induced cardiotoxicity.