Nrf2-Mediated Antioxidant Response and Drug Efflux Transporters Upregulation as Possible Mechanisms of Resistance in Photodynamic Therapy of Cancers.

Photodynamic therapy (PDT) is a groundbreaking approach involving the induction of cytotoxic reactive oxygen species (ROS) within tumors through visible light activation of photosensitizers (PS) in the presence of molecular oxygen. This innovative therapy has demonstrated success in treating various cancers. While PDT proves highly effective in most solid tumors, there are indications that certain cancers exhibit resistance, and some initially responsive cancers may develop intrinsic or acquired resistance to PDT. The molecular mechanisms underlying this resistance are not fully understood. Recent evidence suggests that, akin to other traditional cancer treatments, the activation of survival pathways, such as the KEAP1/Nrf2 signaling pathway, is emerging as an important mechanism of post-PDT resistance in many cancers. This article explores the dual role of Nrf2, highlighting evidence linking aberrant Nrf2 expression to treatment resistance across a range of cancers. Additionally, it delves into the specific role of Nrf2 in the context of photodynamic therapy for cancers, emphasizing evidence that suggests Nrf2-mediated upregulation of antioxidant responses and induction of drug efflux transporters are potential mechanisms of resistance to PDT in diverse cancer types. Therefore, understanding the specific role(s) of Nrf2 in PDT resistance may pave the way for the development of more effective cancer treatments using PDT.

Fermented Rooibos tea (Aspalathus linearis) Ameliorates Sodium Fluoride-Induced Cardiorenal Toxicity, Oxidative Stress, and Inflammation via Modulation of NF-κB/IκB/IκKB Signaling Pathway in Wistar Rats.

High dose of fluoride intake is associated with toxic effects on kidney and cardiac tissues. This study evaluated the potential protective effect of fermented rooibos tea (RTE) on sodium fluoride (NaF)-induced cardiorenal toxicity in rats. Male Wistar rats (n = 56) were randomly allocated into one of seven equal groups: control, NaF (100 mg/kg orally), NaF + RTE (2%, w/v), NaF + RTE (4%, w/v), NaF + lisinopril (10 mg/kg orally), 2% RTE, and 4% RTE. The experiment lasted for 14 days and RTE was administered to the rats as their sole source of drinking fluid. NaF induced cardiorenal toxicity indicated by elevated level of urea, creatinine, LDH, creatinine kinase-MB, and cardiac troponin I in the serum, accompanied by altered histopathology of the kidney and heart. Furthermore, levels of H2O2, malondialdehyde, and NO were elevated, while GSH level was depleted in the kidney and heart due to NaF intoxication. Protein levels of c-reactive protein, TNFα, IL-1B, and NF-κB were increased by NaF in the serum, kidney, and heart. RTE at 2% and 4% (w/v) reversed cardiorenal toxicity, resolved histopathological impairment, attenuated oxidative stress and inhibited formation of pro-inflammatory markers. RTE at both concentrations down-regulates the mRNA expression of NF-κB, and upregulates the mRNA expression of both IκB and IκKB, thus blocking the activation of NF-κB signaling pathway. Taken together, these results clearly suggest that the protective potential of rooibos tea against NaF-induced cardiorenal toxicity, oxidative stress, and inflammation may be associated with the modulation of the NF-κB signaling pathway.

Amelioration of lipopolysaccharide-induced liver injury by aqueous rooibos (Aspalathus linearis) extract via inhibition of pro-inflammatory cytokines and oxidative stress.

BACKGROUND: Acute liver injury occur after intraperitoneal administration of lipopolysaccharide (LPS). Oxidative stress and release of pro-inflammatory cytokines are both implicated in the pathogenesis of LPS-induced acute liver injury. This study investigated the ameliorative effect of fermented rooibos (Aspalathus linearis) extract on LPS-induced acute liver injury. METHOD: Major phenolic compounds in the fermented rooibos extract by HPLC-DAD, as well as the in vitro antioxidant capacity were quantified before the start of the experiment. Male Wistar rats were randomized into 4 groups (n = 10 per group) and given either water or fermented rooibos extract for 4 weeks before LPS injection. Hepatic function markers, including aminotransferases and lactate dehydrogenase, lipid peroxidation markers, antioxidant enzymes, glutathione redox status, as well as cytokine levels were monitored in the rats. RESULTS: Injection of LPS significantly increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH). Oxidative stress, evidenced by increased thiobarbituric acid reactive substances (TBARS) measured as malondialdehyde (MDA) in plasma and liver, and decreased glutathione redox status (GSH: GSSG ratio) in whole blood and liver was induced in LPS-challenged rats. Furthermore, hepatic levels of pro-inflammatory response markers TNF-α, IL-1ß and IL-6 were increased significantly. Pre-feeding the fermented rooibos extract for 4 weeks decreased LPS-induced elevated levels of serum AST and LDH (significantly, p < 0.05) as well as ALT marginally. Consuming rooibos caused an attenuation of the observed increase in plasma and hepatic MDA, decrease in whole blood and liver GSH:GSSG ratio, as well as the changes noted in various antioxidant enzymes. The elevation in TNF-α and IL-6 was significantly suppressed, indicating an inhibition of the induced inflammatory response by rooibos. CONCLUSION: Overall, our data showed that aqueous rooibos extract attenuated LPS-induced liver injury possibly by modulating oxidative stress and suppressing pro-inflammatory cytokines formation.