Effects of naringenin on PI3K/AKT signaling pathway and endoplasmic reticulum stress and its related apoptotic pathways in rats with myocardial ischemia/reperfusion injury

AIM To observe the effect of naringenin on cardiac injury in ischemia/reperfusion （I/R） rats, and to explore whether the role of naringenin is involved in PI3K/AKT signaling pathway and endoplasmic reticulum stress and its related apoptotic pathways. METHODS SD rats （n=48） were randomly divided into sham operation （sham） group, model （I/R） group, naringenin treatment （NAR） group and naringenin+LY294002 （NL） group. Myocardial I/R injury model was prepared by ligation of left anterior descending coronary artery of rats for 30 min followed by reperfusion for 120 min. After reperfusion, the serum levels of cardiac troponin I （cTnI） was measured by ELISA. HE staining, TTC staining and TUNEL staining were used to detect the myocardial histopathological changes, myocardial infarction area and myocardial cell apoptotic rate. The mRNA levels of endoplasmic reticulum stress-related indicators glucose-regulated protein 78 （GRP78）, C/EBP homologous protein （CHOP） and caspase-12 were detected by RT-qPCR. The protein levels of cleaved caspase-3, GRP78, CHOP, caspase-12, p-PI3K and p-AKT were determined by Western blot. RESULTS Compared with I/R group, the serum content of cTnI, myocardial pathological damage, myocardial infarction area and myocardial cell apoptotic rate were significantly reduced （P<0.05）, the protein levels of cleaved caspase-3, GRP78, CHOP and caspase-12 were decreased （P<0.05）, and the protein levels of p-PI3K and p-AKT were increased in NAR group （P<0.05）. LY294002 attenuated the protective effect of naringenin to some extent. CONCLUSION Naringenin reduces myocardial I/R injury in rats possibly by activating PI3K/AKT signaling pathway and subsequently regulating endoplasmic reticulum stress and its related apoptotic pathways.     

柚皮素研究进展

综述柚皮素的提纯方法,及其在医学、化学、食品科学、农药等方面的应用研究进展。     

Molluscicidal activity of Aglaia duperreana and the constituents of its twigs and leaves

The methanol (MeOH) extract of the twigs and leaves of Aglaia duperreana was investigated for its molluscicidal activity against Pomacea canaliculata. The extract was found to exhibit significant molluscicidal activity. The ethyl acetate soluble fraction of the extract showed the most potent molluscicidal activity among different solvent fractions. The bioactivity-guided chemical investigation of the ethyl acetate soluble fraction led to a new triterpenoid along with 15 known compounds. Their structures were elucidated by spectroscopic methods, including one- and two-dimensional nuclear magnetic resonance techniques as well as mass spectroscopic analysis. The molluscicidal activities of compounds 2-16 against P. canaliculata were also investigated. Naringenin trimethyl ether showed significant molluscicidal activity with a median lethal concentration (LC(50)) of 3.9 μg/mL, which was indicated higher potency than the positive control, tea saponin (LC(50)=4.5 μg/mL).     

柚皮素的提取及其抗癌作用研究进展

指出了柚皮素属于二氢黄酮类天然化合物,是柚皮苷的苷元,具有重要的抗炎、抗菌、抗氧化、抗癌等生物学效应。柚皮素的提取方法有酸水解法、酶提取法、超临界CO_2提取法。柚皮素能作用于多种癌细胞,抑制其生长、增殖、迁移,并促进其凋亡,表现出抗癌活性。综述了柚皮素的提取和作用于不同类型的癌细胞的抗癌分子机制,并展望了量子化学技术在柚皮素抗癌作用靶向点的相互作用理论计算研究的应用前景。     

The effects of naringenin and naringin on the glucose uptake and AMPK phosphorylation in high glucose treated HepG2 cells

BackgroundNaringin and its aglycone naringenin are citrus-derived flavonoids with several pharmacological effects. On the other hand, the mechanism for the anti-diabetic effects of naringenin and naringin are controversial and remain to be clarified further.ObjectiveThis study examined the relationship between glucose uptake and AMP-activated protein kinase (AMPK) phosphorylation by naringenin and naringin in high glucose-treated HepG2 cells.MethodsGlucose uptake was measured using the 2-NBDG fluorescent D-glucose analog. The phosphorylation levels of AMPK and GSK3β (Glycogen synthase kinase 3 beta) were observed by Western blotting. Molecular docking analysis was performed to evaluate the binding affinity of naringenin and naringin to the γ-subunit of AMPK.ResultsThe treatment with naringenin and naringin stimulated glucose uptake regardless of insulin stimulation in high glucose-treated HepG2 cells. Both flavonoids increased glucose uptake by promoting the phosphorylation of AMPK at Thr172 and increased the phosphorylation of GSK3β. Molecular docking analysis showed that both naringenin and naringin bind to the γ-subunit of AMPK with high binding affinities. In particular, naringin showed higher binding affinity than the true modulator, AMP with all three CBS domains (CBS1, 3, and 4) in the γ-subunit of AMPK. Therefore, both naringenin and naringin could be positive modulators of AMPK activation, which enhance glucose uptake regardless of insulin stimulation in high glucose-treated HepG2 cells.ConclusionsThe increased phosphorylation of AMPK at Thr172 by naringenin and naringin might enhance glucose uptake regardless of insulin stimulation in high glucose treated HepG2 cells.     

Constituents of the leaves of Holarrhena pubescens

The leaves of Holarrhena pubescens yielded a new naringenin glycoside (1), together with naringin, naringenin 7-O-beta-D-glucoside, lupeol, lupeol beta-hydroxyhexadecanoate and ursolic acid. The structure of 1 was determined by spectral analysis.     

The flavonoid naringenin enhances intercellular colonization of rice roots by<Emphasis Type="Italic"> Azorhizobium caulinodans</Emphasis>

The intercellular colonization of rice roots by Azorhizobium caulinodans and other diazotrophic bacteria has been studied using strains marked with the lacZ reporter gene. A. caulinodans were able to enter the roots of rice at emerging lateral roots (lateral root cracks) by crack entry and this was observed by light microscopy. After colonization of lateral roots, bacteria moved into intercellular space within the cortical cell layer of roots. Naringenin at 1×10^-5 and 5×10^-5 M concentration significantly enhanced root colonization. The role of nodABC and regulatory nodD genes was also studied; lateral root crack (LRC) colonization of rice was shown to be Nod factor and NodD independent. Lateral root crack colonization of rice was also observed with similar frequency following inoculation with Azospirillum brasilense and the colonization by A. brasilense was stimulated by naringenin and other flavonoid molecules.     

柚皮素-镉配合物的合成·表征及其抗氧化作用

[目的]合成柚皮素金属镉配合物,并比较配合物与柚皮素的抗氧化活性。[方法]以柚皮素和乙酸镉为原料在无水乙醇溶液中制备柚皮素-镉配合物,通过紫外(UV)、红外(IR)对配合物进行表征,并采用ABTS法研究其清除自由基的能力。[结果]紫外、红外数据证实柚皮素与镉离子成功配合,且在试验浓度下,配合物对ABTS+·的清除能力随浓度增加而增强,且强于柚皮素。[结论]镉离子成功地与柚皮素形成配合物,其体外抗氧化活性较配体有所增强。     

Restoration of the adipogenic gene expression by naringenin and naringin in 3T3-L1 adipocytes

BackgroundNaringenin and its glycoside naringin are well known citrus flavonoids with several therapeutic benefits. Although the anti-adipogenic effects of naringenin and naringin have been reported previously, the detailed mechanism underlying their anti-adipogenesis effects is poorly understood.ObjectivesThis study examined the anti-adipogenic effects of naringenin and naringin by determining differential gene expression patterns in these flavonoids-treated 3T3-L1 adipocytes.MethodsLipid accumulation and triglyceride (TG) content were determined by Oil red O staining and TG assay. Glucose uptake was measured using a 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose fluorescent d-glucose analog. The phosphorylation levels of AMP-activated protein kinase (AMPK) and acetyl Co-A carboxylase (ACC) were observed via Western blot analysis. Differential gene expressions in 3T3-L1 adipocytes were evaluated via RNA sequencing analysis.ResultsNaringenin and naringin inhibited both lipid accumulation and TG content, increased phosphorylation levels of both AMPK and ACC and decreased the expression level of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) in 3T3-L1 adipocytes. RNA sequencing analysis revealed that 32 up-regulated (> 2-fold) and 17 down-regulated (< 0.6-fold) genes related to lipid metabolism, including Acaca, Fasn, Scd1, Mogat1, Dgat, Lipin1, Cpt1a, and Lepr, were normalized to the control level in naringenin-treated adipocytes. In addition, 25 up-regulated (> 2-fold) and 25 down-regulated (< 0.6-fold) genes related to lipid metabolism, including Acaca, Fasn, Fabp5, Scd1, Srebf1, Hmgcs1, Cpt1c, Lepr, and Lrp1, were normalized to the control level by naringin.ConclusionsThe results indicate that naringenin and naringin have anti-adipogenic potentials that are achieved by normalizing the expression levels of lipid metabolism-related genes that were perturbed in differentiated 3T3-L1 cells.     

Nitrate alters the flavonoid profile and nodulation in pea (Pisum sativum L.)

A rhizosphere application of NO _inf3 ^sup- and/or naringenin affected the Pisum sativum — Rhizobium leguminosarum biovar viciae symbiosis. NO _inf3 ^sup- (5 mM) lowered while naringenin raised the nodulation status (nodule numbers and weight) and nodule efficiency (C₂H₂ reduction activity). However, the inhibitory effect of NO _inf3 ^sup- was to some extent alleviated when applied in combination with naringenin. The plant biomass was increased by the application of NO _inf3 ^sup- and naringenin, either alone or in combination, while a higher root: shoot ratio was observed only in the naringenin-treated plants. Root flavonoids are known to regulate the expression of nod genes; their high-performance liquid chromatography profile was influenced in different ways by NO _inf3 ^sup- and naringenin.