Naringenin is a natural dihydro flavonoid that is abundant in grapefruit.
Previous studies suggested the cognition protective effect of naringenin in various cognitive deficits models, such as type 2 diabetic rat model and chemicals (e.g., lipopolysaccharide, scopolamine) treated rodents. However, the effects of naringenin on aging animals and the potential mechanisms are still unclear. In this study, we investigated the influence of naringenin administration on learning deficits in aging mice. High-fat diet-fed SAMP8 mice were employed as an age-related model of Alzheimer's disease. Dietary administration of 0.2% naringenin for 12 weeks significantly improved the spatial learning and memory performance of the high-fat diet-fed SAMP8 mice in both Barnes Maze test and Morris Water Maze test. Further mechanism research indicated that naringenin reduced Aβ production, tau-hyperphosphorylation, oxidative stress, and neuroinflammation in the brain. This research provides further evidence for the treatment effect of naringenin on Alzheimer's disease. PRACTICAL APPLICATIONS: Naringenin, also known as 4',5,7-thrihydroxyflflavanone, is a natural dihydro flavonoid that is abundant in grapefruit and other citrus fruits. The current study first demonstrated the improvement effect of naringenin on cognition deficits in HFD-fed SAMP8 mice, an aging mouse model. Potential mechanisms were also systematically explained by exploring the amyloid-β (Aβ) accumulation, tau hyperphosphorylation, oxidative stress, and neuroinflammation in the brain of mice. This study provides further evidence for the utilization of naringenin as an effective treatment agent for Alzheimer's disease 1).
Mitochondrial disease contributed greatly to myocardial Reperfusion injury-induced cardiomyocyte apoptosis. This study was designed to elucidate naringenin's mitochondrial protective actions during MI/R with a focus on AMPK-SIRT3 signaling. Sprague-Dawley rats were administered with naringenin (50 mg kg-1 d-1) and subjected to MI/R surgery in the presence or absence of compound C (0.25 mg kg-1, Com.C, an AMPK inhibitor) co-treatment. An in vitro study was performed on H9c2 cardiomyoblasts subjected to simulated ischemia-reperfusion treatment. Before the treatment, the cells were administered with naringenin (80 μmol L-1) with or without SIRT3 siRNA/AMPK1α siRNA transfection. Naringenin improved post-reperfusion left ventricular systolic pressure and the instantaneous first derivative of left ventricular pressure, and reduced the infarction size and myocardial apoptosis index by suppressing mitochondrial oxidative stress damage (as evidenced by decreased mitochondrial cytochrome c release and oxidative markers) and enhancing mitochondrial biogenesis [as evidenced by increased NRF1, TFAM and oxidative phosphorylation subunit complexes (II, III and IV)]. These protective actions were abolished by Com.C (in vivo) or SIRT3 siRNA (in vitro) administration. Further investigation revealed that Com.C (in vivo) or AMPK1α siRNA (in vitro) markedly suppressed PGC-1α and SIRT3 levels while SIRT3 siRNA (in vitro) inhibited SIRT3 expression without significantly changing AMPK phosphorylation and PGC-1α levels. Taken together, we found that naringenin directly inhibits mitochondrial oxidative stress damage and preserves mitochondrial biogenesis, thus attenuating MI/R injury. Importantly, AMPK-SIRT3 signaling played a key role in this process 2).
The effects of naringenin on ER stress as well as oxidative stress under MI/R condition and the detailed mechanisms remain poorly defined. This study investigated the protective effect of naringenin on MI/R-injured heart with a focus on cyclic guanosine monophosphate- (cGMP-) dependent protein kinase (PKG) signaling. Sprague-Dawley rats were treated with naringenin (50 mg/kg/d) and subjected to MI/R surgery with or without KT5823 (2 mg/kg, a selective inhibitor of PKG) cotreatment. Cellular experiment was conducted on H9c2 cardiomyoblasts subjected to simulated ischemia-reperfusion treatment. Before the treatment, the cells were incubated with naringenin (80 μmol/L). PKGIα siRNA was employed to inhibit PKG signaling. Our in vivo and in vitro data showed that naringenin effectively improved heart function while it attenuated myocardial apoptosis and infarction. Furthermore, pretreatment with naringenin suppressed MI/R-induced oxidative stress as well as ER stress as evidenced by decreased superoxide generation, myocardial MDA level, gp91 phox expression, and phosphorylation of PERK, IRE1α, and EIF2α as well as reduced ATF6 and CHOP. Importantly, naringenin significantly activated myocardial cGMP-PKGIα signaling while inhibition of PKG signaling with KT5823 (in vivo) or siRNA (in vitro) not only abolished these actions but also blunted naringenin's inhibitory effects against oxidative stress and ER stress. In summary, our study demonstrates that naringenin treatment protects against MI/R injury by reducing oxidative stress and ER stress via cGMP-PKGIα signaling. Its cardioprotective effect deserves further clinical study 3).