Naringin against doxorubicin-induced hepatotoxicity in mice through reducing oxidative stress, inflammation, and apoptosis via the up-regulation of SIRT1.

Clinical application of doxorubicin is limited because of its potential side effects. The present study examined whether naringin had protective actions on doxorubicin-induced liver injury. Male BALB/c mice and alpha mouse liver 12 (AML-12) cells were used in this paper. The results showed that AML-12 cells treated with naringin significantly reduced cell injury, reactive oxygen species release and apoptosis level; Moreover, naringin notably alleviated liver injury by decreasing aspartate transaminase, alanine transaminase and malondialdehyde, and increasing superoxide dismutase, glutathione and catalase levels. Mechanism researches indicated that naringin increased the expression levels of sirtuin 1 (SIRT1), and inhibited the downstream inflammatory, apoptotic and oxidative stress signaling pathways. Further validation was obtained by knocking down SIRT1 in vitro, which proved the effects of naringin on doxorubicin-induced liver injury. Therefore, naringin is a valuable lead compound for preventing doxorubicin-induced liver damage by reducing oxidative stress, inflammation, and apoptosis via up-regulation of SIRT1.

Naringin Interferes Doxorubicin-Induced Myocardial Injury by Promoting the Expression of ECHS1.

Doxorubicin (DOX) leads to myocardial cell damage and irreversible heart failure, which limits the clinical application of DOX. Naringin has biological functions of inhibiting inflammation, oxidative stress and apoptosis. Our aim was to investigate whether Naringin could prevent DOX-related cardiotoxicity in mice. Naringin was administered by gavage and mice were intraperitoneally injected with doxorubicin (1 mg/kg/day) for 15 days. H&E, Masson, TUNEL and others experiments were examined. NRVMs and H9C2 cells were treated with Naringin and DOX in vitro. Using IF, ELISA and Western Blot to detect the effect of Naringin and ECHS1 on cells. The results showed that Naringin could prevent DOX related cardiac injury, inhibit cardiac oxidative stress, inflammation and apoptosis in vivo and in vitro. Inhibition of ECHS1 could interfere the effect of Naringin on DOX-induced myocardial injury. Naringin may provide a new cardiac protective tool for preventing the cardiotoxicity of anthracycline drugs.

Naringin alleviates acetaminophen-induced acute liver injury by activating Nrf2 via CHAC2 upregulation.

Severe acetaminophen (APAP)-induced hepatic damage is the second most common cause for hepatic transplantation. Clinically, hepatic damage caused by APAP is treated using N-acetyl-L-cysteine, which can induce numerous side effects. Naringin, a bioflavonoid abundant in grapefruit and other citrus fruits, displays marked antiinflammatory and antioxidant activities. Herein, we aimed to investigate the potential mechanism underlying naringin-mediated protection against APAP-induced acute hepatotoxicity. We observed that naringin afforded protection against APAP-induced acute liver failure in mice. Importantly, pretreatment with naringin before APAP administration further increased antioxidant enzyme expression, inhibited the production of proinflammatory cytokines, and activated apoptotic pathways. Furthermore, we observed that the protective effect was associated with the upregulation of cation transport regulator-like protein 2 (CHAC2) and nuclear factor erythroid derived-2-related factor 2 (Nrf2). Notably, CHAC2 knockdown inhibited Nrf2 activation and naringin-mediated antioxidant, antiinflammatory, and antiapoptotic effects in APAP-induced liver injury. Likewise, si-Nrf2 blocked the protective effect of naringin against APAP-induced liver injury. Collectively, our results indicate that naringin may be a potent CHAC2 activator, alleviating APAP-induced hepatitis via CHAC2-mediated activation of the Nrf2 pathway. These data provide new insights into mechanisms through which CHAC2 regulates APAP-induced liver injury by targeting Nrf2, which should be considered a novel therapeutic target.

Naringin attenuates renal interstitial fibrosis by regulating the TGF-ß/Smad signaling pathway and inflammation.

Interstitial fibrosis is a typical feature of all progressive renal diseases. The process of fibrosis is frequently coupled with the presence of pro-fibrotic factors and inflammation. Naringin is a dihydroflavone compound that has been previously reported to exhibit anti-fibrotic effects in the liver, where it prevents oxidative damage. In the present study, a rat model of renal interstitial fibrosis and fibrosis cell model were established to evaluate the effects of naringin on inflammatory proteins and fibrosis markers in kidney of rats and NRK-52E cells, and to elucidate the role of the TGF-ß/Smad signaling pathway in this mechanism. Compared with those in fibrotic NRK-52E cells that were stimulated by transforming growth factor-ß (TGF-ß), gene expression levels of α-smooth muscle actin (α-SMA), collagen 1 (COL1A1), collagen 3 (COL3A1), interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α (TNF-α) were all found to be significantly decreased in fibrotic NRK-52E cells following treatment with naringin (50, 100 and 200 ng/ml). Results from the histopathological studies showed that naringin treatment preserved the renal tissue structure and reduced the degree of fibrosis in the kidney tissues of rats that underwent unilateral ureteral obstruction (UUO). In addition, naringin administration reduced the expression of α-SMA, COL1A1, COL3A1, IL-1ß, IL-6 and TNF-α in the kidneys of rats following UUO. The current study, using western blot analysis, indicated that naringin also downregulated the activation of Smad2/3 and the expression of Smad4, high-mobility group protein B1, activator protein-1, NF-κB and cyclooxygenase-2 whilst upregulating the expression of Smad7 in fibrotic NRK-52E cells and rats in the UUO group. In conclusion, naringin could antagonize renal interstitial fibrosis by regulating the TGF-ß/Smad pathway and the expression of inflammatory factors.