Department of Applied Statistics, Operations Research and Quality, Universitat Politècnica de València, Valencia, Spain.
Department of Microbiology and Ecology, Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BioTecMed), Universidad de Valencia, Valencia, Spain.
Cell Biol Toxicol. 2021 Feb;37(1):129-149. doi: 10.1007/s10565-020-09572-y. Epub 2021 Jan 6.
Patients with liver cirrhosis may develop covert or minimal hepatic encephalopathy (MHE). Hyperammonemia (HA) and peripheral inflammation play synergistic roles in inducing the cognitive and motor alterations in MHE. The cerebellum is one of the main cerebral regions affected in MHE. Rats with chronic HA show some motor and cognitive alterations reproducing neurological impairment in cirrhotic patients with MHE. Neuroinflammation and altered neurotransmission and signal transduction in the cerebellum from hyperammonemic (HA) rats are associated with motor and cognitive dysfunction, but underlying mechanisms are not completely known. The aim of this work was to use a multi-omic approach to study molecular alterations in the cerebellum from hyperammonemic rats to uncover new molecular mechanisms associated with hyperammonemia-induced cerebellar function impairment. We analyzed metabolomic, transcriptomic, and proteomic data from the same cerebellums from control and HA rats and performed a multi-omic integrative analysis of signaling pathway enrichment with the PaintOmics tool. The histaminergic system, corticotropin-releasing hormone, cyclic GMP-protein kinase G pathway, and intercellular communication in the cerebellar immune system were some of the most relevant enriched pathways in HA rats. In summary, this is a good approach to find altered pathways, which helps to describe the molecular mechanisms involved in the alteration of brain function in rats with chronic HA and to propose possible therapeutic targets to improve MHE symptoms.
肝硬化患者可能会出现隐匿性或轻微肝性脑病（MHE）。高血氨症（HA）和外周炎症在诱导 MHE 的认知和运动改变方面发挥协同作用。小脑是 MHE 中受影响的主要大脑区域之一。患有慢性 HA 的大鼠表现出一些运动和认知改变，复制了 MHE 肝硬化患者的神经功能障碍。来自高氨血症（HA）大鼠的小脑中的神经炎症以及神经递质和信号转导的改变与运动和认知功能障碍有关，但潜在机制尚不完全清楚。这项工作的目的是使用多组学方法研究来自高氨血症大鼠的小脑中的分子改变，以揭示与高氨血症诱导的小脑功能障碍相关的新分子机制。我们分析了来自对照和 HA 大鼠的相同小脑的代谢组学、转录组学和蛋白质组学数据，并使用 PaintOmics 工具对信号通路富集进行了多组学综合分析。在 HA 大鼠中，组胺能系统、促肾上腺皮质激素释放激素、环鸟苷酸蛋白激酶 G 途径和小脑免疫系统中的细胞间通讯是最相关的富集途径之一。总之，这是一种很好的方法，可以找到改变的途径，有助于描述慢性高氨血症大鼠大脑功能改变涉及的分子机制，并提出可能的治疗靶点来改善 MHE 症状。
