Nanogold Particles Suppresses 5-Flurouracil-Induced Renal Injury: An Insight into the Modulation of Nrf-2 and Its Downstream Targets, HO-1 and γ-GCS

Abstract

The development of the field of nanotechnology has revolutionized various aspects in the fields of modern sciences. Nano-medicine is one of the primary fields for the application of nanotechnology techniques. The current study sheds light on the reno-protective impacts of gold nano-particles; nanoGold (AuNPs) against 5-flurouracil (5-FU)-induced renal toxicity. Indeed, the use of 5-FU has been associated with kidney injury which greatly curbs its therapeutic application. In the current study, 5-FU injection was associated with a significant escalation in the indices of renal injury, i.e., creatinine and urea. Alongside this, histopathological and ultra-histopathological changes confirmed the onset of renal injury. Both gene and/or protein expression of nuclear factor erythroid 2–related factor 2 (Nrf-2) and downstream antioxidant enzymes revealed consistent paralleled anomalies. AuNPs administration induced a significant renal protection on functional, biochemical, and structural levels. Renal expression of the major sensor of the cellular oxidative status Nrf-2 escalated with a paralleled reduction in the renal expression of the other contributor to this axis, known as Kelch-like ECH-associated protein 1 (Keap-1). On the level of the effector downstream targets, heme oxygenase 1 (HO-1) and gamma-glutamylcysteine synthetase (γ-GCS) AuNPs significantly restored their gene and protein expression. Additionally, combination of AuNPs with 5-FU showed better cytotoxic effect on MCF-7 cells compared to monotreatments. Thus, it can be inferred that AuNPs conferred reno-protective impact against 5-FU with an evident modulatory impact on Nrf-2/Keap-1 and its downstream effectors, HO-1 and γ-GCS, suggesting its potential use in 5-FU regimens to improve its therapeutic outcomes and minimize its underlying nephrotoxicity.

Melatonin protected against kidney impairment induced by 5‐fluorouracil in mice

“…Chemotherapy is the first line of cancer treatment, and 5-FU has demonstrated success with several cancer types. However, its clinical utility is limited due to undesirable side effects such as nephrotoxicity (El-Sherbiny et al, 2021). Anticancer drug toxicity is caused by several factors, including oxidative stress, inflammation, and apoptosis.…”

α-Lipoic Acid Protects against Cyclosporine A-Induced Hepatic Toxicity in Rats: Effect on Oxidative Stress, Inflammation, and Apoptosis

“…Nrf2 is a transcription factor that regulates several genes encoding for detoxifying enzymes and antioxidant proteins such as HO-1, glutathione S-transferase, glutathione peroxidase modulation of NADPH oxidase, and the Nrf2/HO-1 pathway by vanillin in cisplatin-induced nephrotoxicity in rats [35,36]. Moreover, Nrf2 regulates the balance of apoptotic/antiapoptotic proteins, controlling cellular apoptosis [37].…”

Vitamin K2 (MK-7) Intercepts Keap-1/Nrf-2/HO-1 Pathway and Hinders Inflammatory/Apoptotic Signaling and Liver Aging in Naturally Aging Rat

“…Under normal physiological conditions, Keap1 binds to Nrf2 to form a complex in a low activity state. In contrast, various oxidative and/or pathological insults induces the modification of Keap1 cysteine residue, triggering Nrf2 phosphorylation and translocation to the nucleus, where it mediates the transcription process to control the downstream gene expression of a series of antioxidant enzymes of HO-1 [ 46 ]. These events help in quenching ROS; removing other cellular harmful substances and activating the antioxidative defense mechanism, antiapoptotic, anti-inflammatory and other cell protection mechanisms [ 47 ].…”