Liu Chun, Russell Robert M, Wang Xiang-Dong
Nutrition and Cancer Biology Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.
J Nutr. 2004 Oct;134(10):2705-10. doi: 10.1093/jn/134.10.2705.
We demonstrated previously that smoke exposure and/or high-dose beta-carotene supplementation decreases levels of retinoic acid and retinoic acid receptor beta (RARbeta) protein, but increase levels of c-Jun and proliferating cellular nuclear antigen protein in the lungs of ferrets. In contrast, low-dose beta-carotene can prevent the decreased lung retinoic acid and the smoke-induced lung lesions. In the present study, we investigated whether smoke exposure and/or beta-carotene supplementation could affect Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and p53 in the lungs of ferrets. Ferrets were subjected to cigarette smoke exposure and either a high or low dose of beta-carotene (2 x 3 factorial design) for 6 mo. There were greater protein levels of phosphorylated JNK, p38, and c-Jun, but lower levels of MAPK phophatase-1 (MKP-1) in groups exposed to smoke and/or high dose beta-carotene. Both phosphorylated-p53 and total p53 were substantially increased in the lungs of these groups. In contrast, low-dose beta-carotene greatly attenuated the smoke-induced phosphorylation of JNK, p38, c-Jun, p53, and total p53, accompanied by upregulated MKP-1. Smoke exposure increased MAPK kinase-4 (MKK4) phosphorylation regardless of beta-carotene supplementation. These data indicate that restoration of retinoic acid and MKP-1 by low-dose beta-carotene in the lungs of ferrets may prevent the smoke-induced activation of the JNK-dependent signaling pathway, p38 MAPK, and the associated phosphorylation of p53, thereby lowering the risk of the smoke-related lung lesions. These data provide supportive evidence that the beneficial vs. detrimental effects of beta-carotene supplementation are related to the dosage of beta-carotene administered.
我们之前证明，烟雾暴露和/或高剂量β-胡萝卜素补充会降低雪貂肺组织中视黄酸和视黄酸受体β（RARβ）蛋白的水平，但会增加c-Jun和增殖细胞核抗原蛋白的水平。相比之下，低剂量β-胡萝卜素可预防肺组织中视黄酸水平降低以及烟雾诱导的肺部病变。在本研究中，我们调查了烟雾暴露和/或β-胡萝卜素补充是否会影响雪貂肺组织中的Jun氨基末端激酶（JNK）、p38丝裂原活化蛋白激酶（MAPK）和p53。将雪貂进行香烟烟雾暴露，并给予高剂量或低剂量β-胡萝卜素（2×3析因设计），持续6个月。在暴露于烟雾和/或高剂量β-胡萝卜素的组中，磷酸化JNK、p38和c-Jun的蛋白水平更高，但丝裂原活化蛋白激酶磷酸酶-1（MKP-1）的水平更低。这些组的肺组织中磷酸化p53和总p53均显著增加。相比之下，低剂量β-胡萝卜素可显著减弱烟雾诱导的JNK、p38、c-Jun、p53和总p53的磷酸化，同时MKP-1上调。无论是否补充β-胡萝卜素，烟雾暴露都会增加丝裂原活化蛋白激酶激酶-4（MKK4）的磷酸化。这些数据表明，低剂量β-胡萝卜素使雪貂肺组织中的视黄酸和MKP-1恢复，可能会预防烟雾诱导的JNK依赖性信号通路、p38 MAPK的激活以及p53的相关磷酸化，从而降低与烟雾相关的肺部病变风险。这些数据提供了支持性证据，表明β-胡萝卜素补充的有益与有害作用与所给予的β-胡萝卜素剂量有关。
