The Preventive Effects and the Mechanisms of Action of Navel Orange Peel Hydroethanolic Extract, Naringin, and Naringenin in N-Acetyl-p-aminophenol-Induced Liver Injury in Wistar Rats

Abstract

N-Acetyl-p-aminophenol (APAP) or acetaminophen is the most common drug ingredient worldwide. It is found in more than 600 different over-the-counter and prescription medicines. Its long-term and overdose use is highly toxic and may result in liver injury. Thus, this study was designed to assess the preventive effects and to suggest the mechanisms of action of the navel orange peel hydroethanolic extract, naringin, and naringenin in APAP-induced hepatotoxicity in male Wistar rats. APAP was administered to male Wistar rats at a dose level of 0.5 g/kg body weight (b.w.) by oral gavage every other day for 4 weeks. APAP-administered rats were treated with the navel orange peel hydroethanolic extract (50 mg/kg b.w.), naringin (20 mg/kg b.w.), and naringenin (20 mg/kg b.w.) by oral gavage every other day during the same period of APAP administration. The treatments of APAP-administered rats with the peel extract, naringin, and naringenin produced a significant decrease in the elevated serum AST, ALT, ALP, LDH, and GGT activities as well as total bilirubin and TNF-α levels while they induced a significant increase in the lowered serum albumin and IL-4 levels. The treatments also resulted in a significant decrease in the elevated liver lipid peroxidation and enhanced the liver GSH content and SOD, GST, and GPx activities as compared with APAP-administered control; the peel extract was the most potent in improving the liver LPO, GSH content, and GPx activity. In addition, the three treatments significantly downregulated the elevated hepatic proapoptotic mediators p53, Bax, and caspase-3 and significantly upregulated the suppressed antiapoptotic protein, Bcl-2, in APAP-administered rats. In association, the treatments markedly amended the APAP-induced liver histopathological deteriorations that include hepatocyte steatosis, cytoplasmic vacuolization, hydropic degeneration, and necrosis together with mononuclear leucocytic and fibroblastic inflammatory cells’ infiltration. In conclusion, the navel orange peel hydroethanolic extract, naringin, and naringenin may exert their hepatopreventive effects in APAP-administered rats via enhancement of the antioxidant defense system and suppression of inflammation and apoptosis.

Platelet-Rich Plasma Ameliorates Monosodium Iodoacetate-Induced Ankle Osteoarthritis in the Rat Model via Suppression of Inflammation and Oxidative Stress

“…The MIA injection to the rats provokes the increase in the inflammatory cytokines, while it suppresses the anti-inflammatory cytokines, thereby developing the inflammation process. In addition to the necrotic effects of TNF- α , it activates the tumor necrosis factor receptor or death receptors, thereby activating the extrinsic pathway of apoptosis ( Figure 13 ) [ 43 , 44 ]. Furthermore, the inflammatory environment and the increased levels of TNF- α and IL-17 could result in a decrease in the formation and release of growth factors (GFs) such as transforming growth factor (TGF) leading to reduced chondrogenesis and formation of chondrocytes from mesenchymal stem cells ( Figure 13 ) [ 45 ].…”

A Dihydroflavonoid Naringin Extends the Lifespan of C. elegans and Delays the Progression of Aging-Related Diseases in PD/AD Models via DAF-16

“…Naringin, also known as citrus or isohesperidin, is a kind of dihydroflavonoid ( Figure 1(a) ), which is a natural pale yellow pigment that exists in the peel and fruit of Citrus grandis, Citrus paradisi, and Citrus (Rutaceae) aurantium [ 13 ]. Naringin exhibits multiple biological activities and pharmacological effects, including antitumor [ 14 ], antihypercholesterolemic [ 15 ], desensitization [ 16 ], antiallergy, antiphotoaging [ 17 ], cytoprotective [ 18 ], anti-inflammatory, heart-protective [ 7 , 13 , 19 , 20 ], and neuroprotective activities [ 21 – 23 ]. Naringin could also regulate glucose and lipid metabolism [ 24 ] and oxidative stress [ 25 ].…”

Innovative application of helium-neon laser: enhancing the germination of Adansonia digitata and evaluating the hepatoprotective activities in mice

“…The HPLC-MS analysis of the A. digitata extract confirmed the presence of phenolic acids such as gallic acid, coffeic acid, and flavonoids such as rutin, quercetin, and naringenin which had an anti-apoptotic effect. Naringenin was reported to be the most potent in decreasing Bax overexpression (Ahmed et al 2019). The anti-apoptotic effect of rutin and quercetin was reported by Gelen et al (2017) through its effect on caspase-3 and Bcl-2 genes.…”