Yassine Mona, Hassan Soha A, Yücel Lea Aylin, Purath Fathima Faiba A, Korf Horst-Werner, von Gall Charlotte, Ali Amira A H
Institute of Anatomy II, Medical Faculty, Heinrich Heine University, Moorenstraße 5, 40225 Düsseldorf, Germany.
Department of Zoology, Faculty of Science, Suez University, P.O. Box 43221, Suez 43533, Egypt.
Biomedicines. 2024 Sep 27;12(10):2202. doi: 10.3390/biomedicines12102202.
: Chronic liver diseases such as hepatic tumors can affect the brain through the liver-brain axis, leading to neurotransmitter dysregulation and behavioral changes. Cancer patients suffer from fatigue, which can be associated with sleep disturbances. Sleep is regulated via two interlocked mechanisms: homeostatic regulation and the circadian system. In mammals, the hypothalamic suprachiasmatic nucleus (SCN) is the key component of the circadian system. It generates circadian rhythms in physiology and behavior and controls their entrainment to the surrounding light/dark cycle. Neuron-glia interactions are crucial for the functional integrity of the SCN. Under pathological conditions, oxidative stress can compromise these interactions and thus circadian timekeeping and entrainment. To date, little is known about the impact of peripheral pathologies such as hepatocellular carcinoma (HCC) on SCN. : In this study, HCC was induced in adult male mice. The key neuropeptides (vasoactive intestinal peptide: VIP, arginine vasopressin: AVP), an essential component of the molecular clockwork (Bmal1), markers for activity of neurons (c-Fos), astrocytes (GFAP), microglia (IBA1), as well as oxidative stress (8-OHdG) in the SCN were analyzed by immunohistochemistry at four different time points in HCC-bearing compared to control mice. : The immunoreactions for VIP, Bmal1, GFAP, IBA1, and 8-OHdG were increased in HCC mice compared to control mice, especially during the activity phase. In contrast, c-Fos was decreased in HCC mice, especially during the late inactive phase. : Our data suggest that HCC affects the circadian system at the level of SCN. This involves an alteration of neuropeptides, neuronal activity, Bmal1, activation of glia cells, and oxidative stress in the SCN.
慢性肝病如肝肿瘤可通过肝脑轴影响大脑，导致神经递质失调和行为改变。癌症患者会出现疲劳，这可能与睡眠障碍有关。睡眠通过两种相互关联的机制进行调节：稳态调节和昼夜节律系统。在哺乳动物中，下丘脑视交叉上核（SCN）是昼夜节律系统的关键组成部分。它产生生理和行为的昼夜节律，并控制它们与周围光/暗周期的同步。神经元-神经胶质细胞相互作用对于SCN的功能完整性至关重要。在病理条件下，氧化应激会损害这些相互作用，从而影响昼夜节律计时和同步。迄今为止，关于诸如肝细胞癌（HCC）等外周病理学对SCN的影响知之甚少。
在本研究中，成年雄性小鼠被诱导患上HCC。通过免疫组织化学在四个不同时间点分析了荷瘤小鼠与对照小鼠SCN中的关键神经肽（血管活性肠肽：VIP、精氨酸加压素：AVP）、分子时钟机制的重要组成部分（Bmal1）、神经元活性标志物（c-Fos）、星形胶质细胞（GFAP）、小胶质细胞（IBA1）以及氧化应激（8-OHdG）。
与对照小鼠相比，HCC小鼠中VIP、Bmal1、GFAP、IBA1和8-OHdG的免疫反应增加，尤其是在活动期。相比之下，HCC小鼠中c-Fos减少，尤其是在非活动后期。
我们的数据表明，HCC在SCN水平上影响昼夜节律系统。这涉及神经肽的改变、神经元活性、Bmal1、神经胶质细胞的激活以及SCN中的氧化应激。
