Lonp1 and Sig-1R contribute to the counteraction of ursolic acid against ochratoxin A-induced mitochondrial apoptosis

IF 3.9 3区医学 Q2 FOOD SCIENCE & TECHNOLOGY

Food and Chemical Toxicology Pub Date : 2023-02-01 DOI:10.1016/j.fct.2022.113592

Qipeng Zhang , Wenying Chen , Boyang Zhang , Yiwen Zhang , Yuqing Xiao , Yichen An , Lingyun Han , Huiqiong Deng , Song Yao , Hongwei Wang , Xiao Li Shen

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引用次数: 5

Abstract

Ochratoxin A (OTA), a secondary fungal metabolite with nephrotoxicity, is widespread in numerous kinds of feeds and foodstuffs. Ursolic acid (UA), a water-insoluble pentacyclic triterpene acid, exists in a wide range of food materials and medicinal plants. Our earlier researches provided preliminary evidence that mitochondria- and mitochondria-associated endoplasmic reticulum membranes (MAMs)-located stress-responsive Lon protease 1 (Lonp1) had a protective function in OTA-induced nephrotoxicity, and the renoprotective function of UA against OTA partially due to Lonp1. However, whether other MAMs-located protiens, such as endoplasmic reticulum stress (ERS)-responsive Sigma 1-type opioid receptor (Sig-1R), contribute to the protection of UA against OTA-induced nephrotoxicity together with Lonp1 needs further investigation. In this study, the cell viability, reactive oxygen species, and protein expressions of human proximal tubule epithelial-originated kidney-2 (HK-2) cells varied with OTA and/or UA/CDDO-me/AVex-73/Sig-1R siRNA treatments were determined. Results indicated that a 24 h-treatment of 5 μM OTA could significantly induce mitochondrial-mediated apoptosis via repressing Lonp1 and Sig-1R, thereby enhancing the protein expressions of GRP78, p-PERK, p-eIF2α, CHOP, IRE1α, and Bax, and inhibiting the protein expression of Bcl-2 in HK-2 cells, which could be remarkably relieved by a 2 h-pre-treatment of 4 μM UA (P < 0.05). In conclusion, through mutual promotion between Lonp1 and Sig-1R, UA could effectively relieve OTA-induced apoptosis in vitro and break the vicious cycle between oxidative stress and ERS, which activated the mitochondrial apoptosis pathway.

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Lonp1和Sig-1R参与熊果酸对抗赭曲霉毒素a诱导的线粒体凋亡

赭曲霉毒素A (OTA)是一种具有肾毒性的次生真菌代谢物，广泛存在于多种饲料和食品中。熊果酸(UA)是一种不溶于水的五环三萜酸，广泛存在于食品原料和药用植物中。我们早期的研究提供了初步证据，证明线粒体和线粒体相关内质网膜(MAMs)上的应激响应性Lon蛋白酶1 (Lonp1)在OTA诱导的肾毒性中具有保护作用，而UA对OTA的肾保护作用部分是由于Lonp1。然而，其他mams定位的蛋白，如内质网应激(ERS)应答Sigma -1型阿片受体(sig1 - 1r)，是否与Lonp1一起有助于UA抵抗ta诱导的肾毒性，还需要进一步研究。本研究测定了OTA和/或UA/CDDO-me/AVex-73/Sig-1R siRNA处理下人近端小管上皮源性肾-2 (HK-2)细胞的细胞活力、活性氧和蛋白表达的变化。结果表明，5 μM OTA处理24 h可通过抑制Lonp1和sig1r显著诱导线粒体介导的细胞凋亡，从而提高GRP78、P - perk、P - eif2 α、CHOP、IRE1α和Bax蛋白的表达，抑制HK-2细胞中Bcl-2蛋白的表达，而4 μM UA预处理2 h可显著缓解这一现象(P <0.05)。综上所述，UA可以通过Lonp1和Sig-1R之间的相互促进，有效缓解ota诱导的体外细胞凋亡，打破氧化应激与ERS之间的恶性循环，激活线粒体凋亡通路。

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来源期刊

Food and Chemical Toxicology 工程技术-毒理学

CiteScore

10.90

自引率

4.70%

发文量

651

审稿时长

31 days

期刊介绍： Food and Chemical Toxicology (FCT), an internationally renowned journal, that publishes original research articles and reviews on toxic effects, in animals and humans, of natural or synthetic chemicals occurring in the human environment with particular emphasis on food, drugs, and chemicals, including agricultural and industrial safety, and consumer product safety. Areas such as safety evaluation of novel foods and ingredients, biotechnologically-derived products, and nanomaterials are included in the scope of the journal. FCT also encourages submission of papers on inter-relationships between nutrition and toxicology and on in vitro techniques, particularly those fostering the 3 Rs. The principal aim of the journal is to publish high impact, scholarly work and to serve as a multidisciplinary forum for research in toxicology. Papers submitted will be judged on the basis of scientific originality and contribution to the field, quality and subject matter. Studies should address at least one of the following: -Adverse physiological/biochemical, or pathological changes induced by specific defined substances -New techniques for assessing potential toxicity, including molecular biology -Mechanisms underlying toxic phenomena -Toxicological examinations of specific chemicals or consumer products, both those showing adverse effects and those demonstrating safety, that meet current standards of scientific acceptability. Authors must clearly and briefly identify what novel toxic effect (s) or toxic mechanism (s) of the chemical are being reported and what their significance is in the abstract. Furthermore, sufficient doses should be included in order to provide information on NOAEL/LOAEL values.