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Abstract The intensive exposure of the liver cells to any type of noxae, such as viruses, drugs, alcohols, and xenobiotics could induce hepatic inflammation through the upregulation of gene expression of several fibrotic and inflammatory mediators. So, our study assessed the role of silymarin on the inflammatory response induced by carbon tetrachloride (CCl4) as an example of xenobiotics on liver tissues in male rats. Forty-eight Wister male rats (weight: 130 ± 10) were housed for 14 days and then divided randomly into six groups: control, SLY: rats received only silymarin orally for 12 weeks (daily), CO: rats were injected with corn oil for 8 weeks (3 times weekly), CCl4: rats were injected with CCl4 solubilized in corn oil for 8 weeks (day by day), Treated: rats received silymarin for 4 weeks after CCl4 injection, Protected: rats received silymarin for 4 weeks before and 8 weeks during CCl4 injection. When the treatment period for the rats was over, they underwent scarification after anesthesia. Then, the sera were extracted from the collected blood for the determination of irisin levels, liver functions, and lipid profiles. Liver tissues were separated for the histopathological examinations, the determination of oxidative stress (OS) parameters content, and the relative gene expression of inflammatory cytokines; nuclear factor kappa (NF)-κB, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, cyclooxygenase (COX)-2, and transforming growth factor beta (TGF-β). The findings showed that silymarin reduced liver inflammation by overcoming the OS process and inflammatory cytokines production which was stimulated by CCl4. These results were confirmed by histopathology of liver tissues.

Alzheimer’s disease (AD) is a devastating illness with limited therapeutic interventions. The aim of this study is to investigate the pathophysiological mechanisms underlying AD and explore the potential neuroprotective effects of cocoa, either alone or in combination with other nutraceuticals, in an animal model of aluminum-induced AD. Rats were divided into nine groups: control, aluminum chloride (AlCl3) alone, AlCl3 with cocoa alone, AlCl3 with vinpocetine (VIN), AlCl3 with epigallocatechin-3-gallate (EGCG), AlCl3 with coenzyme Q10 (CoQ10), AlCl3 with wheatgrass (WG), AlCl3 with vitamin (Vit) B complex, and AlCl3 with a combination of Vit C, Vit E, and selenium (Se). The animals were treated for five weeks, and we assessed behavioral, histopathological, and biochemical changes, focusing on oxidative stress, inflammation, Wnt/GSK-3β/β-catenin signaling, ER stress, autophagy, and apoptosis. AlCl3 administration induced oxidative stress, as evidenced by elevated levels of malondialdehyde (MDA) and downregulation of cellular antioxidants (Nrf2, HO-1, SOD, and TAC). AlCl3 also upregulated inflammatory biomarkers (TNF-α and IL-1β) and GSK-3β, leading to increased tau phosphorylation, decreased brain-derived neurotrophic factor (BDNF) expression, and downregulation of the Wnt/β-catenin pathway. Furthermore, AlCl3 intensified C/EBP, p-PERK, GRP-78, and CHOP, indicating sustained ER stress, and decreased Beclin-1 and anti-apoptotic B-cell lymphoma 2 (Bcl-2) expressions. These alterations contributed to the observed behavioral and histological changes in the AlCl3-induced AD model. Administration of cocoa, either alone or in combination with other nutraceuticals, particularly VIN or EGCG, demonstrated remarkable amelioration of all assessed parameters. The combination of cocoa with nutraceuticals attenuated the AD-mediated deterioration by modulating interrelated pathophysiological pathways, including inflammation, antioxidant responses, GSK-3β-Wnt/β-catenin signaling, ER stress, and apoptosis. These findings provide insights into the intricate pathogenesis of AD and highlight the neuroprotective effects of nutraceuticals through multiple signaling pathways.