College of Animal Sciences, Zhejiang University; Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou 310058, China.
Food Funct. 2024 Jun 17;15(12):6459-6474. doi: 10.1039/d4fo00783b.
Deoxynivalenol (DON) pollution is prevalent in crops, and can induce oxidative stress and intestinal injury. Hesperidin is one of the major flavonoids in citrus fruits that has various biological activities such as antioxidant and anti-inflammatory activities. However, whether hesperidin could alleviate DON-induced intestinal injury and the mechanism remain unclear. Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) have attracted attention for their crucial signaling points to regulate ER-mitochondria calcium transfer. This study aims to evaluate the effects of hesperidin on the intestinal barrier, mitochondrial function, MAMs, and inositol 1,4,5-triphosphate receptor (IP3R)-mitochondrial calcium uniporter (MCU) calcium axis in the intestine of piglets exposed to DON. Twenty-four piglets were randomly divided into four groups in a 2 × 2 factorial arrangement for a 21-d experiment: Control: basal diet; hesperidin group: basal diet + 300 mg kg hesperidin; DON: basal diet + 1.5 mg kg DON; DON + hesperidin group: basal diet + 1.5 mg kg DON + 300 mg kg hesperidin. The data showed that when compared with the DON group, hesperidin improved growth performance and the intestinal barrier, alleviated intestinal oxidative stress and ER stress, and decreased the serum alanine aminotransferase (ALT) level ( < 0.05). Hesperidin also alleviated mitochondrial dysfunction and ferroptosis in the intestine of piglets exposed to DON ( < 0.05). Importantly, hesperidin prevented excessive MAM formation by downregulating the protein levels of Mitofusin 2 (Mfn2) and glucose-regulated protein 75 (GRP75), decreasing the ratio of the mitochondria with MAMs/total mitochondria and the ratio of MAM length/mitochondrial perimeter and lengthening the mitochondria-ER distance in MAMs ( < 0.05). Furthermore, hesperidin regulated the IP3R-glucose-regulated protein 75 (GRP75)-voltage-dependent anion channel 1 (VDAC1)-MCU calcium axis by decreasing the protein levels of GRP75 and MCU and the calcium level of the mitochondria compared with the DON group ( < 0.05). An experiment was conducted to further explore whether IP3R-mediated ER-mitochondria calcium transfer was involved in the protective effects of hesperidin on the intestinal epithelium barrier and mitochondria. Data showed that hesperidin may exert protective effects on the intestinal epithelium barrier and mitochondria inhibiting ER-mitochondrial calcium transfer mediated by IP3Rs. These data suggested that hesperidin could alleviate MAM-mediated mitochondrial calcium overload, thereby improving mitochondrial function and alleviating oxidative stress and intestinal injury in DON-challenged piglets.
脱氧雪腐镰刀菌烯醇（DON）污染普遍存在于农作物中，可诱导氧化应激和肠道损伤。橙皮苷是柑橘类水果中主要的类黄酮之一，具有抗氧化和抗炎等多种生物活性。然而，橙皮苷是否能缓解 DON 诱导的肠道损伤及其机制尚不清楚。线粒体相关内质网（ER）膜（MAMs）因其在调节 ER-线粒体钙转移中的关键信号点而受到关注。本研究旨在评估橙皮苷对仔猪暴露于 DON 后肠道屏障、线粒体功能、MAMs 和肌醇 1,4,5-三磷酸受体（IP3R）-线粒体钙单向转运体（MCU）钙轴的影响。24 头仔猪随机分为 4 组，采用 2×2 析因设计进行 21d 试验：对照组：基础日粮；橙皮苷组：基础日粮+300mg/kg 橙皮苷；DON 组：基础日粮+1.5mg/kg DON；DON+橙皮苷组：基础日粮+1.5mg/kg DON+300mg/kg 橙皮苷。结果表明，与 DON 组相比，橙皮苷改善了生长性能和肠道屏障，减轻了肠道氧化应激和 ER 应激，降低了血清丙氨酸氨基转移酶（ALT）水平（<0.05）。橙皮苷还减轻了 DON 暴露仔猪的线粒体功能障碍和铁死亡（<0.05）。重要的是，橙皮苷通过下调融合蛋白 2（Mfn2）和葡萄糖调节蛋白 75（GRP75）的蛋白水平，降低带 MAMs 的线粒体与总线粒体的比例、MAMs 长度/线粒体周长的比例和 MAMs 中线粒体-内质网距离，从而防止了 MAMs 的过度形成（<0.05）。此外，与 DON 组相比，橙皮苷通过降低 GRP75 和 MCU 的蛋白水平以及线粒体钙水平来调节 IP3R-葡萄糖调节蛋白 75（GRP75）-电压依赖性阴离子通道 1（VDAC1）-MCU 钙轴（<0.05）。进一步的实验表明，橙皮苷可能通过抑制 IP3Rs 介导的 ER-线粒体钙转移，对肠道上皮屏障和线粒体发挥保护作用。这些数据表明，橙皮苷可以通过抑制 IP3Rs 介导的 ER-线粒体钙转移来减轻 MAM 介导的线粒体钙超载，从而改善 DON 应激仔猪的线粒体功能和减轻氧化应激和肠道损伤。
