Antioxidation and Anti-Inflammatory Activity of Prussian Blue Nanozymes to Alleviate Acetaminophen-Induced Acute Liver Injury

Abstract

Acetaminophen (APAP), a common antipyretic and analgesic drug, is considered the most common cause of drug-induced liver injury (DILI). The mechanism of liver injury induced by APAP is mainly related to oxidative stress and inflammatory reaction. Herein, we report a simple and efficient one-step synthesis of Prussian blue (PB) nanozymes with multiple antioxidant enzymatic activities that effectively treat APAP-induced DILI. At the cellular level, reaching 10 μg/mL PB nanozymes can effectively scavenge intracellular reactive oxygen species (ROS), reduce mitochondrial membrane potential drop, and inhibit hepatocyte apoptosis. According to in vivo experimental studies, the levels of serum biochemical indicators and histopathological examination of DILI mice livers showed that 12.5 mg/kg PB nanozymes could effectively inhibit liver necrosis and 25 mg/kg PB nanozymes achieved the same therapeutic effect as 300 mg/kg NAC. More importantly, compared with NAC, PB nanozymes can still attenuate APAP-induced acute liver injury in mice after APAP-induced acute liver injury in mice for 3 h. Therefore, PB nanozymes can effectively prolong the therapeutic time window, revealing the potential of PB nanozymes in clinical applications for advanced DILI treatment. Furthermore, the therapeutic mechanism studies have shown that PB nanozymes with abundant and variable valence states could not only directly scavenge ROS but also through the Keap1-Nrf2/HO-1 pathway to reduce oxidative stress. Moreover, the decreased expression levels of myeloperoxidase and F4/80 in the liver, which are markers of neutrophil and macrophage infiltration, indicated that the Prussian blue nanozymes modulates inflammation to protect against APAP-induced acute liver injury. Consequently, our findings suggested that PB nanozymes have excellent clinical application prospects for acetaminophen-induced acute liver injury.

Prussian Blue Nanoparticle: From a Photothermal Conversion Agent and a Drug Delivery System, to a Bioactive Drug

“…Our researches show the prevention/treatment effect and preliminary mechanism of nano PB in tumors, ,− neurodegenerative disease (Alzheimer’s disease and Parkinson’s disease), , cardiocerebral vascular disease (ischemic stroke, vascular restenosis), ,, bone-related degenerative disease (osteoarthritis and osteoporosis), − digestive system diseases (inflammatory bowel disease, acute pancreatitis, and liver injury), ,− and skin damage . In addition, the bioactivities of nano PB were also revealed. ,,− The enormous application potential of nano PB in disease prevention and treatment has also been verified by other scholars. ,,− In the future, we need to further explore the mechanism of nano PB in more diseases and reveal its bioactivities.…”

“…In addition, the strategy has also been validated in drug-induced liver injury and other models. Pretreatment with nano PB intravenously reduced oxidative stress by activating the Nrf2 pathway, reducing the expression of peroxidase and F480 in the liver and counteracting inflammation, to maintain the normal microenvironment of the liver, thereby preventing drug-induced liver damage. , …”

Reactive Oxygen Species Scavenging Nanozymes: Emerging Therapeutics for Acute Liver Injury Alleviation

“…In order to better study the mechanism and treatment of acute liver injury, different kinds of acute liver injury animal models have been established, including drug-induced liver injury (eg APAP-induced liver injury, [58][59][60] anthracyclineinduced liver injury 61 ), chemical-induced liver injury (eg CCl 4 -induced liver injury 62,63 ), immune-induced liver injury (eg lipopolysaccharide (LPS)-induced liver injury, 64,65 D-galactosamine-induced liver injury, 66 concanavalin A-induced liver injury 67,68 ), alcohol-induced liver injury, 69,70 and hepatic ischemia-reperfusion injury. 7,35,71 Transition Metal-Based Nanozymes…”

“…For example, Umezaki et al prepared hydrophilic C 60 (OH) 10 nanoparticles with ROS-scavenging properties for the treatment of an APAP-induced liver injury. 110 Zhou et al developed biocompatible [60]/ [70] fullerenols with superior ROS-scavenging ability for the alleviation of hepatotoxicity induced by doxorubicin chemotherapy (Figure 8B). 111 Long et al developed hydrophilic carbohydrate-derived nanoparticles with good colloidal stability and blood circulation lifetime, effective liver delivery ability, and excellent ROS scavenging capability to prevent the mice from hepatic ischemiareperfusion injury (Figure 8E).…”

“…Feng et al reports a simple and efficient one-step synthesis of Prussian blue (PB) nanozymes with multiple antioxidant enzymatic activities that effectively treat APAP-induced DILI ( Figure 3D ). 60 According to in vivo experimental studies, the levels of serum biochemical indicators and histopathological examination of DILI mice livers showed that 12.5 mg/kg PB nanozymes could effectively inhibit liver necrosis and 25 mg/kg PB nanozymes achieved the same therapeutic effect as 300 mg/kg NAC. It is well-established that the substitution of iron with transition metals, including cobalt, nickel, manganese, copper, and zinc, enables the synthesis of diverse Prussian blue analogs (PBA) exhibiting distinct chemical compositions yet sharing similar crystal structures.…”