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Potential of Icariin Metabolites from Epimedium koreanum Nakai as Antidiabetic Therapeutic Agents.

ABSTRACT: The therapeutic properties of Epimediumkoreanum are presumed to be due to the flavonoid component icariin, which has been reported to have broad pharmacological potential and has demonstrated anti-diabetic, anti-Alzheimer's disease, anti-tumor, and hepatoprotective activities. Considering these therapeutic properties of icariin, its deglycosylated icaritin and glycosylated flavonoids (icaeriside II, epimedin A, epimedin B, and epimedin C) were evaluated for their ability to inhibit protein tyrosine phosphatase 1B (PTP1B) and ?-glucosidase. The results show that icaritin and icariside II exhibit potent inhibitory activities, with 50% inhibition concentration (IC50) values of 11.59 ± 1.39 ?M and 9.94 ± 0.15 ?M against PTP1B and 74.42 ± 0.01 and 106.59 ± 0.44 ?M against ?-glucosidase, respectively. With the exceptions of icaritin and icariside II, glycosylated flavonoids did not exhibit any inhibitory effects in the two assays. Enzyme kinetics analyses revealed that icaritin and icariside II demonstrated noncompetitive-type inhibition against PTP1B, with inhibition constant (Ki) values of 11.41 and 11.66 ?M, respectively. Moreover, molecular docking analysis confirmed that icaritin and icariside II both occupy the same site as allosteric ligand. Thus, the molecular docking simulation results were in close agreement with the experimental data with respect to inhibition activity. In conclusion, deglycosylated metabolites of icariin from E. koreanum might offer therapeutic potential for the treatment of type 2 diabetes mellitus.

SUBMITTER: Kim DH

PROVIDER: S-EPMC6152727 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Potential of Icariin Metabolites from Epimedium koreanum Nakai as Antidiabetic Therapeutic Agents.

Kim Da Hye DH Jung Hyun Ah HA Sohn Hee Sook HS Kim Jin Woong JW Choi Jae Sue JS

Molecules (Basel, Switzerland) 20170613 6

The therapeutic properties of Epimediumkoreanum are presumed to be due to the flavonoid component icariin, which has been reported to have broad pharmacological potential and has demonstrated anti-diabetic, anti-Alzheimer's disease, anti-tumor, and hepatoprotective activities. Considering these therapeutic properties of icariin, its deglycosylated icaritin and glycosylated flavonoids (icaeriside II, epimedin A, epimedin B, and epimedin C) were evaluated for their ability to ...[more]

PMID: 28608833

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Project description:Epimedii Folium is widely used worldwide as an herbal supplement, and the risk of its induced liver damage has emerged in recent years. Our preliminary study has found that, among several Epimedii Folium species specified in the Chinese Pharmacopoeia, Epimedium koreanum Nakai has a more severe propensity for hepatotoxicity. However, the mechanism of hepatotoxicity of Epimedium koreanum Nakai is still unclear. In this study, untargeted metabolomics was performed to analyze the serum and liver tissue to explore the mechanism of hepatotoxicity of Epimedium koreanum Nakai. The results of experiments in vivo showed that, after 28 days of exposure to Epimedium koreanum Nakai ethanol extract (EEE), the liver weight, levels of AST, ALP, TBIL, etc. in serum of rats in the EEE group were significantly increased, as well as severe cytoplasmic vacuolation appeared in the liver tissue, which suggested that EEE has significant hepatotoxicity. Subsequently, the results of metabolomics revealed significant changes in the metabolic profile in the liver and serum of rats after EEE exposure, in which metabolites in serum such as flavin mononucleotide, phenylacetylglycine, glutathione, l-tryptophan, and sphingomyelin were able to accurately identify liver injury caused by EEE and could be used as serum markers to reflect EEE-induced liver injury. The KEGG pathway enrichment analysis revealed that EEE caused extensive effects on rats' metabolic pathways. Some of the most affected pathways included glutathione metabolism, glutamate metabolism pathway, primary bile acid biosynthesis pathway, and sphingolipid metabolism pathway, which were all directed to the biological process of ferroptosis. Then, the main markers related to ferroptosis in the liver were examined, and the results demonstrated that the content of malondialdehyde was significantly increased, the activity of superoxide dismutase was significantly reduced, the ferroptosis inhibitory proteins GPX4 and System xc - were significantly downregulated, and the ferroptosis-promoting protein ACSL4 was significantly up-regulated. Judging from these results, we concluded that the mechanism of hepatotoxicity of Epimedium koreanum Nakai was probably related to the induction of ferroptosis in hepatocytes.

Project description:Nitrogen is a crucial nutrient element for plant growth and productivity, with both excess and deficiency in nitrogen fertilizer application posing adverse effects on plants and the environment. The internal mechanisms by which the medicinal plant Epimedium pubescens (E. pubescens) adapts to varying nitrogen levels remain unclear. This study employed one-year-old E. pubescens as the experimental material to systematically analyze the changes in plant growth traits, carbon metabolites, and Icariin-Flavonoids content under different exogenous nitrogen levels. Furthermore, it examined the transcriptional changes in gene expression within E. pubescens in response to varying nitrogen levels. The results showed that under moderate nitrogen levels (7.5 mmol/L NO3-), E. pubescens exhibited increased biomass accumulation and flavonoid synthesis. However, deficient or excessive nitrogen levels (0, 22.5 mmol/L NO3-) significantly inhibited photosynthesis in E. pubescens, reducing the content of starch, soluble sugars, and Icariin-Flavonoids, leading to decreased biomass and accompanied by changes in leaf color (pale green or browning). Transcriptome analysis revealed the underlying molecular mechanisms of these changes in plants regulated by different nitrogen levels. Nitrogen deficiency and excess triggered distinct transcriptional response patterns, with the number of differentially expressed genes (DEGs) peaking at S2 (36 days) under nitrogen deficiency and significantly declining at S3 (48 days), while the number of DEGs under excess nitrogen continuously increased over time from S1 to S3 (12-48 days). Both conditions significantly affected the expression of genes related to carbon and nitrogen metabolism, flavonoid synthesis, and stress response. Based on the correlation analysis of expression levels of genes related to these pathways, growth traits, and metabolite content indicators, we constructed regulatory network diagrams for carbon-nitrogen metabolism and Icariin-flavonoid metabolism-related genes. Furthermore, we identified hub genes that may be involved in regulating Icariin-flavonoid metabolism in response to nitrogen levels, such as UGT (Ebr06G044290), EpF3H (Ebr04G062950), EpCHS5 (Ebr03G073940) (Fig. 9A), UGT (Ebr06G044660), and EpUGT13_A (Ebr06G044210). Additionally, among the DEGs obtained at the S3 stage, we discovered the transcription factors MYB1_CROXC (Ebr04G001770) and MYB12_ARATH (Ebr01G065030). We constructed their associated gene networks under different nitrogen levels, which may primarily regulate the expression of genes like UGT, CHS, and F3H involved in the flavonoid synthesis stage of E. pubescens under varying nitrogen conditions. In summary, this study has revealed the growth performance and the variation patterns of Icariin-Flavonoid metabolism in E. pubescens in response to different exogenous nitrogen levels, as well as their complex underlying mechanisms. Additionally, key genes involved in regulating the synthesis of flavonol glycosides in E. pubescens by nitrogen levels have been identified. This provides an important basis for a deeper understanding of the mechanisms of nitrogen regulation on the growth and secondary metabolism of medicinal plants. Furthermore, it offers theoretical support and potential genetic resources for the efficient utilization of nitrogen fertilizers in E. pubescens cultivation and the breeding of high-nitrogen-use-efficiency varieties.

Dataset Information

Potential of Icariin Metabolites from Epimedium koreanum Nakai as Antidiabetic Therapeutic Agents.

Publications

Potential of Icariin Metabolites from Epimedium koreanum Nakai as Antidiabetic Therapeutic Agents.

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