Preclinical experiments and clinical trials demonstrated that angiotensin II AT receptor overactivity associates with aging and cellular senescence and that AT receptor blockers (ARBs) protect from age-related brain disorders. In a primary neuronal culture submitted to glutamate excitotoxicity, gene set enrichment analysis (GSEA) revealed expression of several hundred genes altered by glutamate and normalized by candesartan correlated with changes in expression in Alzheimer's patient's hippocampus. To further establish whether our data correlated with gene expression alterations associated with aging and senescence, we compared our global transcriptional data with additional published datasets, including alterations in gene expression in the neocortex and cerebellum of old mice, human frontal cortex after age of 40, gene alterations in the Werner syndrome, rodent caloric restriction, Ras and oncogene-induced senescence in fibroblasts, and to tissues besides the brain such as the muscle and kidney. The most significant and enriched pathways associated with aging and senescence were positively correlated with alterations in gene expression in glutamate-injured neurons and, conversely, negatively correlated when the injured neurons were treated with candesartan. Our results involve multiple genes and pathways, including CAV1, CCND1, CDKN1A, CHEK1, ICAM1, IL-1B, IL-6, MAPK14, PTGS2, SERPINE1, and TP53, encoding proteins associated with aging and senescence hallmarks, such as inflammation, oxidative stress, cell cycle and mitochondrial function alterations, insulin resistance, genomic instability including telomere shortening and DNA damage, and the senescent-associated secretory phenotype. Our results demonstrate that AT receptor blockade ameliorates central mechanisms of aging and senescence. Using ARBs for prevention and treatment of age-related disorders has important translational value.
- Angiotensin receptor blockers
- Glutamate excitotoxicity
- p53 neuroprotection
Er-Zhi-Wan (EZW), a famous traditional Chinese formulation, is used to prevent, or to treat, various liver and kidney diseases for its actions of replenishing liver and kidney. However, the mechanisms of treating Liver-kidney Yin deficiency syndrome (LKYDS) of EZW have not been comprehensively investigated. In this study, a broad range metabolomics strategy coupled with network analysis was established to investigate possible mechanisms of EZW in treating LKYDS. The rat models of LKYDS were established using the mixture of thyroxine and reserpine, and the changes of biochemical indices in serum and histopathology were detected to explore the effects of EZW. Next, a broad range metabolomics strategy based on RPLC-Q-TOF/MS and HILIC-Q-TOF/MS has been developed to find the possible significant metabolites in the serum and urine of LKYDS rats. Then, network analysis was applied to visualize the relationships between identified serum and urine metabolites and in detail to find hub metabolites, which might be responsible for the effect of EZW on rats of LKYDS. Furthermore, the shortest path of "disease gene-pathway protein-metabolite" was built to investigate the possible intervention path of EZW from the systematic perspective. Five hub metabolites, namely, arachidonic acid, L-arginine, testosterone, taurine and oxoglutaric acid, were screened out and could be adjusted to recover by EZW. After that, the shortest path starting from disease genes and ending in metabolites were identified and disclosed, and the genes of aging such as CAV1 and ACO1 were selected to explain the pathological mechanism of LKYDS. Broad range metabolomics coupled with network analysis could provide another perspective on systematically investigating the molecular mechanism of EZW in treating LKYDS at metabolomics level. In addition, EZW might prevent the pathological process of LKYDS through regulating the disturbed metabolic pathway and the aging genes such as CAV1 and ACO1, which may be potential targets for EZW in the treatment of LKYDS.
- Disease Models, Animal
- Drugs, Chinese Herbal
- Mass Spectrometry
- Medicine, Chinese Traditional
- Rats, Sprague-Dawley
- Yin Deficiency
- Broad range metabolomics
- Liver-kidney Yin deficiency syndrome
- Network analysis