Chinmedomics Strategy for Elucidating the Pharmacological Effects and Discovering Bioactive Compounds From Keluoxin Against Diabetic Retinopathy

Abstract

Keluoxin (KLX) is an active agent in the treatment of diabetic retinopathy (DR). However, its mechanism, targets, and effective constituents against DR are still unclear, which seriously restricts its clinical application. Chinmedomics has the promise of explaining the pharmacological effects of herbal medicines and investigating the effective mechanisms. The research results from electroretinography and electron microscope showed that KLX could reduce retinal dysfunction and pathological changes by the DR mouse model. Based on effectiveness, we discovered 64 blood biomarkers of DR by nontargeted metabolomics analysis, 51 of which returned to average levels after KLX treatment including leukotriene D4 and A4, l-tryptophan, 6-hydroxymelatonin, l-phenylalanine, l-tyrosine, and gamma-linolenic acid (GLA). The metabolic pathways involved were phenylalanine metabolism, steroid hormone biosynthesis, sphingolipid metabolism, etc. Adenosine monophosphate-activated protein kinase (AMPK), extracellular signal-regulated protein kinase1/2 (ERK1/2), phosphatidylinositol-3-kinase (PI3K), and protein 70 S6 kinase (p70 S6K) might be potential targets of KLX against DR. This was related to the mammalian target of rapamycin (mTOR) signaling and AMPK signaling pathways. We applied the chinmedomics strategy, integrating serum pharm-chemistry of traditional Chinese medicine (TCM) with metabolomics, to discover astragaloside IV (AS-IV), emodin, rhein, chrysophanol, and other compounds, which were the core effective constituents of KLX when against DR. Our study was the first to apply the chinmedomics strategy to discover the effective constituents of KLX in the treatment of DR, which fills the gap of unclear effective constituents of KLX. In the next step, the research of effective constituents can be used to optimize prescription preparation, improve the quality standard, and develop an innovative drug.

Metabolomics of various samples advancing biomarker discovery and pathogenesis elucidation for diabetic retinopathy

“…Untargeted metabolomic analysis on serum was used to investigate the effect and mechanism of medicine or natural active components on DR as well (90). As an example, Kong et al discovered 64 serum biomarkers of DR in C57BL/KsJ-db/db mice based on the confirmed effectiveness of Keluoxin (KLX), 51 of which moved toward normal levels by KLX intervention, such as gamma-linolenic acid, L-tyrosine, L-tryptophan, L-phenylalanine, and others (98). By further analysis, six core metabolic pathways like tryptophan metabolism were deemed as vital ones significantly associated with the KLX effect on DR.…”

Metabolomic comparison followed by cross-validation of enzyme-linked immunosorbent assay to reveal potential biomarkers of diabetic retinopathy in Chinese with type 2 diabetes

“…However, the changes of IAA in serum level of DR have been rarely reported. Kong et al suggested that increasing the levels of tryptophan and IAA and decreasing the level of indole acetaldehyde by drugs may modulate tryptophan metabolism to protect the nervous system of T2DM samples (32). Besides, there was a human trial showed that oral IAA can reduce blood glucose in diabetic samples (33).…”

Mass spectrometry-based metabolomics for discovering active ingredients and exploring action mechanism of herbal medicine

“…In this study, six potential vasodilator compounds with relaxant effects on mesenteric arteries were selected using multivariate statistical analysis, including corynoxeine, isocorynoxeine, isorhynchophylline, rhynchophylline, and hirudin. Sun et al (2022) identified glycyrrhizic acid, kaempferol, cinnamaldehyde, catechin daidzein, and caffeic acid as the primary therapeutic efficacy components of Lingguizhugan decoction in the treatment of heart failure using UHPLC-Q-TOF-MS/MS in conjunction with cell experiments and digital storage mining; Kong et al (2022) used UPLC-QTOF-MS to explore the core active ingredients of Keluoxin (KLX) in the treatment of diabetic retinopathy. The results showed that rhein, astragaloside IV, emodin, chrysophanol and other compounds may be the pharmacodynamic basis of KLX.…”