<p>Network Pharmacology Combined with Transcriptional Analysis to Unveil the Biological Basis of Astaxanthin in Reducing the Oxidative Stress Induced by Diabetes Mellitus</p>

Abstract

Purpose Astaxanthin (Ast) has been reported to reduce oxidative stress induced by diabetes mellitus (DM). The aim of this research was to give a systematic overview of the biological basis for this process. Methods Ast-targeted proteins were collected from the BATMAN database, Comparative Toxicogenomics Database, and STITCH database. Putative DM-related protein targets were collected from the GeneCards database. A DM-rat model was then built with streptozotocin (STZ) combined with a high-sugar, high-fat diet for 30 days. Total cholesterol (TC), triglycerides (TGs), and insulin levels were examined using whole tail-vein blood from overnight-fasted rats. SOD, GSH, and MDA activy was detected in liver tissue ( p <0.05). In addition, we used RNA-sequencing analysis to detect gene-transcription level in liver tissue of rats and GO biological process analysis to show all the log 2 FC≥2 genes in the Ast-fed DM rats compared with the DM group using the STRING database. Ast-intersecting targets were collected with Venn analysis. Docking analysis between Ast and targeted proteins was down with the SwissDock server. Ast targets–pathway networks were built using Cytoscape 3.7.2 software. Results A total of 120 Ast-targeted proteins and 13,784 DM-related targets were collected. Ast functioned in reducing TC, TG, and MDA levels, promoting SOD activity and GSH expression, and alleviating islet-cell injury in Ast-fed DM rats compared with DM control rats. Furthermore, genes involved in MAPK, TNF, AMPK, and FOXO signaling pathways were differently expressed in Ast-treated DM rats compared with DM rats. The differentially expressed genes were enriched in euchromatin, thyroid cancer, and metaphase-plate congression. Three Ast-intersecting targets — Col5A1, Nqo1, and Notch2 — were then identified. We found possible binding patterns of Ast with Nqo1 and Notch2, respectively. Ast targets–pathway networks were finally built to show a systematic overview of how Ast works in multiple pathways to reduce oxidative stress. Taken together, Ast is predicted to target Col5A1, Nqo1, and Notch2 to form a network of systemic pharmacological effects to: 1) promote insulin-releasing balance and relieve insulin resistance, 2) reduce testicular cell apoptosis, and 3) maintain normal size in marginal-zone B cells and inhibit autoimmune DM, all of which contribute to the balance of lipid metabolism and reduction of oxidative stress in DM patients. Conclusion Ast functions in reducing oxidative stress in DM rats by regulating a variety of targets to form a comprehensive antioxidative network.

The diverse functionality of NQO1 and its roles in redox control

“…Interestingly, recent work has shown that the carotenoid astaxanthin reduces oxidative stress in a streptozotocin-induced diabetes model combined with high sugar and high fat. Of 120 targeted proteins and more than 13,000 diabetes mellitus targets, network analysis combined with transcriptional analysis identified NQO1 as one of the 3 key targets together with Col5A1 and Notch 2 responsible for the intersecting networks leading to astaxanthin-induced decreases in oxidative stress and reduced insulin resistance [ 248 ].

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Multi-omics regulatory networks reveal the key driver genes in the development of type 2 diabetes

“…COL5A1 encodes an alpha chain for one of the low abundance fibrillar collagens. Previous work revealed that Col5A1, Nqo1, and Notch2 modulated by Ast may promote insulin-releasing balance, relieve insulin resistance, and maintain normal size in marginal-zone B cells [42]. Besides, diseases associated with COL5A1 gene/protein from the curated CTD Gene-Disease Associations dataset suggested the potential association between COL5A1 and diabetes mellitus with a standardized value of 1.24401 [43].…”

Astaxanthin: The possible effects of this carotenoid on disease, inflammation and aging control. A meta-analysis

“…The ability of ATX to decrease inflammatory processes as well as reduce free radicals has been extensively reported in scientific literature. In our present review we found several studies in animals and humans where ATX had remarkable results in enzymes activity such as SOD [31,32,33] , GPx [27,34] , transcription factor signaling proteins such as AMPK [33] , control of inflammatory processes by inhibiting NF-kβ [35] , TNF-α [36,37] among others. These markers appeared four or more times in published in vivo works found in this review.…”

“…These markers appeared four or more times in published in vivo works found in this review. We could observe that ATX can control the mechanisms of apoptosis in some diseases, such as dementia [33] , non-alcoholic hepatic steatosis [37] , type 2 diabetes [34] , glaucoma [38,39] , myocardial mitochondrial dysfunction [40] , myocardial injury [41,42] traumatic brain injury [33] , muscular dystrophy [43] , pancreatitis [44] and among many others. These mechanisms in most cases are associated with the control of NF-kB, TNF-a and consequently caspase-3.…”

“…The effect of ATX in the pathologies mentioned above can be attributed to its ability to maintain preserved mitochondrial functions. ATX has been shown to be extremely effective in restoring the activity of GPx enzymes, as well as SOD in removing ROS and preserve mitochondrial structure [27,34] . Some studies in the past have linked the effects of ROS production to the shortening of telomeres [30] .…”