Upregulation of Nrf2/HO-1 Signaling and Attenuation of Oxidative Stress, Inflammation, and Cell Death Mediate the Protective Effect of Apigenin against Cyclophosphamide Hepatotoxicity.

Liver injury is among the adverse effects of the chemotherapeutic agent cyclophosphamide (CP). This study investigated the protective role of the flavone apigenin (API) against CP-induced liver damage, pointing to the involvement of Nrf2/HO-1 signaling. Rats were treated with API (20 and 40 mg/kg) for 15 days and received CP (150 mg/kg) on day 16. CP caused liver damage manifested by an elevation of transaminases, alkaline phosphatase (ALP), and lactate dehydrogenase (LDH), and histological alterations, including granular vacuolation, mononuclear cell infiltration, and hydropic changes. Hepatic reactive oxygen species (ROS), malondialdehyde (MDA), and nitric oxide (NO) were increased and glutathione (GSH) and antioxidant enzymes were decreased in CP-administered rats. CP upregulated the inflammatory markers NF-κB p65, TNF-α, IL-6, and iNOS, along with the pro-apoptotic Bax and caspase-3. Pre-treatment with API ameliorated circulating transaminases, ALP, and LDH, and prevented histopathological changes in CP-intoxicated rats. API suppressed ROS, MDA, NO, NF-κB p65, iNOS, inflammatory cytokines, oxidative DNA damage, Bax, and caspase-3 in CP-intoxicated rats. In addition, API enhanced hepatic antioxidants and Bcl-2 and boosted the Nrf2 and HO-1 mRNA abundance and protein. In conclusion, API is effective in preventing CP hepatotoxicity by attenuating oxidative stress, the inflammatory response, and apoptosis. The hepatoprotective efficacy of API was associated with the upregulation of Nrf2/HO-1 signaling.

Impact of the phytochemicals cocktail "breast safeguard" in regulating the interplay between redox signalling and murine adenocarcinoma cell proliferation, survival and angiogenesis.

Phytochemicals are natural plant extracts with a potent antioxidant, anti-inflammatory and anticancer characteristics by acting as a cell signalling modulator. This study aims to evaluate the effect of a commercial cocktail of phytochemicals "Breast safeguard" (BSG) in upregulating the expression of antioxidant enzymes to counteract signalling pathways that promote Ehrlich cells progression. The potent antioxidant activity and total phenolics and flavonoids contents of BSG was chemically validated, BSG treated mice showed a significant reduction at the tumor size, along with significant reduction in the expression of prognostic markers CEA and TNFα and induction of cell cycle arrest at G1/S phase as well as downregulation of Ki67. BSG supplementation significantly diminished H2O2, NO, MDA levels and upregulated the expression of SOD, CAT, GPx and GSH antioxidant enzymes in plasma and tumor tissues. BSG treatment markedly activated P53/Bax/Bcl2/c-caspase 3 signalling for cell apoptosis and attenuated the expression of antiapoptotic survivin protein. Meanwhile, BSG significantly diminished the expression of VEGF as an indication of angiogenesis inhibition. In conclusion, BSG exerted a significant upregulation of antioxidant enzymes which may be involved in upregulating P53/Bax/c-caspase 3 expression and attenuation of cell proliferation and angiogenesis.

Punicalagin ameliorates the elevation of plasma homocysteine, amyloid-ß, TNF-α and apoptosis by advocating antioxidants and modulating apoptotic mediator proteins in brain.

The present study investigated the neuroprotective role of punicalagin, a major polyphenolic compound of pomegranate on methionine-induced brain injury. Hyperhomocysteinemia (HHcy) was induced in two months old male BALB c mice by methionine supplementation in drinking water (1 g/kg body weight) for 30 days. Punicalagin (1 mg/kg) was injected i.p every other day concurrently with methionine. Punicalagin significantly prevented the rise in the levels of homocysteine, amyloid-ß and TNF-α. HHcy is associated with a decrease in the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (PGx) and glutathione reductase (GR) and glutathione (GSH) levels in the brains of methionine-treated mice while these antioxidants are increased by punicalagin supplementation. The treatment with punicalagin significantly decreased oxidative stress as indicated by decreased malondialdehyde and protein carbonyl formation in the brain. Compared with methionine-treated animals, mice that treated with methionine and punicalagin remarkably displayed less apoptosis, indicated by the lower level of proapoptotic protein (Bax, caspases- 3, 9 and p53) and higher levels of antiapoptotic Bcl-2 protein than those in hyperhomocysteinemic mice. The potent bioactivity of punicalagin extends to protect neuronal DNA as evidenced by the inhibition of the increase of comet parameters compared to the methionine-treated mice. In conclusion, punicalagin protected from methionine-induced HHcy and brain damage with an ability to repress apoptosis by modulating apoptotic mediators and maintaining DNA integrity in the brain of mice.