Beneficial effects of naringenin in liver diseases: Molecular mechanisms

Abstract

Liver diseases are caused by different etiological agents, mainly alcohol consumption, viruses, drug intoxication or malnutrition. Frequently, liver diseases are initiated by oxidative stress and inflammation that lead to the excessive production of extracellular matrix (ECM), followed by a progression to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). It has been reported that some natural products display hepatoprotective properties. Naringenin is a flavonoid with antioxidant, antifibrogenic, anti-inflammatory and anticancer properties that is capable of preventing liver damage caused by different agents. The main protective effects of naringenin in liver diseases are the inhibition of oxidative stress, transforming growth factor (TGF-β) pathway and the prevention of the transdifferentiation of hepatic stellate cells (HSC), leading to decreased collagen synthesis. Other effects include the inhibition of the mitogen activated protein kinase (MAPK), toll-like receptor (TLR) and TGF-β non-canonical pathways, the inhibition of which further results in a strong reduction in ECM synthesis and deposition. In addition, naringenin has shown beneficial effects on nonalcoholic fatty liver disease (NAFLD) through the regulation of lipid metabolism, modulating the synthesis and oxidation of lipids and cholesterol. Moreover, naringenin protects from HCC, since it inhibits growth factors such as TGF-β and vascular endothelial growth factor (VEGF), inducing apoptosis and regulating MAPK pathways. Naringenin is safe and acts by targeting multiple proteins. However, it possesses low bioavailability and high intestinal metabolism. In this regard, formulations, such as nanoparticles or liposomes, have been developed to improve naringenin bioavailability. We conclude that naringenin should be considered in the future as an important candidate in the treatment of different liver diseases.

New insights into TGF-β/Smad signaling in tissue fibrosis

“…It has been demonstrated that both Smad2 and Smad3 were strongly activated in liver fibrosis [49]. Smad3 appeared to be a key element responsible for fibrosis [19,49,50]. Smad4 interacted with Smad2/3 and participated in the transcription of downstream pro-fibrotic target genes, while Smad7 negatively regulated TGF-β/Smad signaling in two different ways.…”

Naringenin downregulates inflammation-mediated nitric oxide overproduction and potentiates endogenous antioxidant status during hyperglycemia

“…NRN, as compared to MET treatment, provided a better prevention against hepatotoxicity in alloxan exposed rats. NRN has been evaluated against various causative factors increasing the levels of these enzymes in different in vivo and in vitro studies [27]. Similar, we investigated levels of kidney function markers namely; blood urea nitrogen (BUN) and creatinine (Fig.…”

The effect of naringenin on the role of nuclear factor (erythroid‐derived 2)‐like2 (Nrf2) and haem oxygenase 1 (HO‐1) in reducing the risk of oxidative stress‐related radiotoxicity in the spleen of rats

“…As a dietary component, flavonoids have health‐promoting properties related to their anti‐oxidation and anti‐ tumor roles in many chronic diseases . Naringenin (NRG), a flavonoid found in high concentrations in grapefruit, has been reported for the hypocholesterolemic, antiestrogenic, hypolipidemic, antihypertensive, and anti‐inflammatory activities . Various studies have indicated that NRG exhibited higher antioxidant capacity and hydroxyl and superoxide radical scavenger efficiency.…”

“…Naringenin (NRG) is a flavanone chemically known as 5,7‐dihydroxy‐2‐(4‐hydroxyphenyl) chromen‐4, which is found in abundance in grapefruit and other citrus fruits Lee et al 2001. It was reported that NRG has anti‐tumoral, anti‐inflammatory, hepato‐protective, and antioxidant effect . Accordingly, the purpose of this study was to evaluate the role of naringenin (NRG) against γ‐radiation‐induced redox state and haematological alterations in the spleen tissue of Wistar albino rats.…”

“…It was reported that NRG has antitumoral, anti-inflammatory, hepato-protective, and antioxidant effect. [19][20][21][22] Accordingly, the purpose of this study was to evaluate the role of naringenin (NRG) against γ-radiation-induced redox state and haematological alterations in the spleen tissue of Wistar albino rats.…”