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AbstractEpimedium is widely used in traditional Chinese medicine and contains rich bioactive compounds. These compounds often have a methyl group at their 4’-OH position catalyzed by methyltransferases. Therefore, studying methyltransferases in Epimedium plants is of great significance. In this study, a flavonol methyltransferase, EpOMT4, was isolated from Epimedium pseudowushanense B.L. Guo. The recombinant enzyme regiospecifically transferred a methyl group to the 4’-OH position of 8-prenylkaempferol forming icaritin. The study demonstrates that enzymatic methylation of flavonoids in Epimedium plants holds significant potential and could provide a promising alternative method for the biosynthetic production of bioactive methylated prenylflavonoids. [ABSTRACT FROM AUTHOR]

Epimedium is used in traditional Chinese medicine. Epimedium polysaccharides have a variety of physiological properties. This study compared three different processes for the extraction of polysaccharides from Epimedium spp., including ultrasonic, aqueous enzymatic, and microwave extraction, to optimize the extraction conditions and determine the optimal extraction method. The optimal parameters for each method were analyzed. The results showed that the optimal process for ultrasonic extraction was an ultrasonic power of 250 W, an extraction time of 60 min, a temperature of 50 °C, and a solid–liquid ratio of 1:35. The optimal conditions for the aqueous enzymatic method were a papain concentration of 70 U/mL, extraction time of 70 min, a temperature of 50 °C, and a material-to-liquid ratio of 1:30, while those for microwave extraction were a microwave power of 650 W, an extraction time of 50 min, a temperature of 40 °C, and a material-to-liquid ratio of 1:25. The polysaccharide yields were 4.85%, 4.72%, and 3.98% for the three methods, respectively, indicating that ultrasonic extraction resulted in the highest yield of polysaccharides from Epimedium brevicornum. After purification with DEAE-cellulose, the polysaccharide yields were 4.13%, 3.67%, and 3.12%, respectively. A comprehensive comparison demonstrated the superiority of the ultrasonic extraction method in terms of both extraction yield and purification efficiency. Characterization of the extracted Epimedium polysaccharides showed the presence of five monosaccharides, i.e., glucose, galactose, mannose, galacturonic acid, and rhamnose, and a number average molecular weight Mn of 1.65 × 105 Da and weight average molecular weight Mw of 6.61 × 105 Da. These results provide a scientific basis for the in-depth study and application of Epimedium polysaccharides. [ABSTRACT FROM AUTHOR]

In this study, four previously undescribed flavonoids, named epimesatines P (1), Q (2), R (3), and S (4), were isolated from the aerial parts of Epimedium sagittatum Maxim. Their structures and absolute configurations were confirmed via spectroscopic analyses, quantum chemical electronic circular dichroism (ECD) calculations, Mo2(OAc)4–induced ECD, and Rh2(OCOCF3)4–induced ECD experiments. Epimesatines Q and R were characterized by the presence of furan rings. A cytotoxicity assay demonstrated that epimesatines P–S exhibited significant inhibitory effects on the viability of MCF-7 human breast cancer cells, with IC50 values ranging from 1.27 to 50.3 μM. Notably, epimesatines Q and R exhibited superior efficacy against MCF-7 cells compared to epimesatines P and S, suggesting that the presence of furan rings may enhance their activity against MCF-7 cells. Specifically, epimesatine Q displayed a more potent inhibitory effect at 1.27 μM compared to a positive control, docetaxel, which had an IC50 of 2.13 μM, highlighting its potential as a therapeutic agent for breast cancer. Importantly, none of the tested compounds exhibited obvious toxicity toward MCF-10A human breast epithelial cells. Furthermore, compounds 1, 3, and 4 were found to significantly inhibit the expression of sphingosine kinase 1 (Sphk1) in MCF-7 cells. [ABSTRACT FROM AUTHOR]

Two new prenylated flavonol glycosides, namely Desmethylicaritin-3-O-β-D-glucopyranosyl-(1→3)-α-L(4″-O-acetyl) rhamnopyranosyl-7-O-β-D(6′′′′-O-acetyl)-glucopyranoside (1) and 5,7,3′,4′-tetrahydroxyl-8-(3,3-dimethylallyl)-flavonol-3-O-α-L-rhamnopyranoside (2), and one with no NMR spectral data reported (3) were isolated from Epimedium koreanum Nakai. Their structures were elucidated by 1D, 2D NMR and HRESIMS analysis. The identification of the sugar moieties was carried out by means of acid hydrolysis and HPLC analysis of their derivatives. The anti-pulmonary fibrosis activities result showed that compound 2 had significant inhibitory effects on A549 cell fibrosis, which was similar to that of the positive control drug, pirfenidone. [ABSTRACT FROM AUTHOR]

Epimedium Folium has been extensively utilized for medicinal purposes in China for a significant period. This review undertakes a comprehensive examination of literature pertaining to Epimedium and its metabolites over the past decade, drawing from databases such as PubMed. Through meticulous organization and synthesis of pertinent research findings, including disease models, pharmacological effects, and related aspects, this narrative review sheds light on the principal pharmacological activities and associated mechanisms of Epimedium in safeguarding the reproductive system, promoting bone health, mitigating inflammation, and combating tumors and viral infections. Consequently, this review contributes to a more profound comprehension of the recent advances in Epimedium research. [ABSTRACT FROM AUTHOR]

Epimedium is a traditional Chinese medicine with a wide range of clinical applications; however, there have been numerous reports of adverse reactions in recent years. The most common side effect of Epimedium is liver injury. In this study, the liquid chromatography–mass spectrometry (LC–MS) method has been established to study the components of Epimedium and to identify the components absorbed into the blood of rats. Bioinformatics was used to screen out potential toxic components, and the integrating metabolomics method was used to explore the molecular mechanism of Epimedium‐induced liver injury. The chemical constituents of Epimedium were identified by LC–MS, and 62 compounds were obtained, including 57 flavonoids, four organic acids and one alkaloid. The toxicity network of "Epimedium–component–target–liver injury" was constructed using bioinformatics research methods, and then the key hepatotoxic component icaritin was identified. Integrating metabolomics was used to investigate the changes in the metabolic profile of L‐02 cells with different durations of icaritin administration compared with the control group, and 106 different metabolites were obtained. A total of 14 potential biomarkers significantly associated with cell survival were screened by Pearson correlation analysis combined with the L‐02 cell survival rate. Our study preliminarily revealed the mechanism of hepatotoxicity induced by Epimedium. [ABSTRACT FROM AUTHOR]

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Purpose: Epimedium brevicornu Maxim. is a perennial persistent C3 plant of the genus Epimedium Linn. in the family Berberaceae that exhibits severe physiological and morphological seed dormancy.We placed mature E. brevicornu seeds under nine stratification treatment conditions and explored the mechanisms of influence by combining seed embryo growth status assessment with related metabolic pathways and gene co-expression analysis. Results: We identified 3.9 °C as the optimum cold-stratification temperature of E. brevicornu seeds via a chilling unit (CU) model. The best treatment was variable-temperature stratification (10/20 °C, 12/12 h) for 4 months followed by low-temperature stratification (4 °C) for 3 months (4-3). A total of 63801 differentially expressed genes were annotated to 2587 transcription factors (TFs) in 17 clusters in nine treatments (0-0, 0-3, 1-3, 2-3, 3-3, 4-3, 4-2, 4-1, 4-0). Genes specifically highly expressed in the dormancy release treatment group were significantly enriched in embryo development ending in seed dormancy and fatty acid degradation, indicating the importance of these two processes. Coexpression analysis implied that the TF GRF had the most reciprocal relationships with genes, and multiple interactions centred on zf-HD and YABBY as well as on MYB, GRF, and TCP were observed. Conclusion: In this study, analyses of plant hormone signal pathways and fatty acid degradation pathways revealed changes in key genes during the dormancy release of E. brevicornu seeds, providing evidence for the filtering of E. brevicornu seed dormancy-related genes. [ABSTRACT FROM AUTHOR]

Epimedium brevicornu Maxim (E. brevicornu) is a plant of Epimedium L. in Berberidaceae, which is widely distributed and has high medicinal value and many important clinical applications. In this experiment, a novel flavonoid compound (1) was isolated and identified the chemical structure from E. brevicornu. The extract of E. brevicornu was performed on normal silica column chromatography, ODS silica column chromatography, Sephadex LH-20 column chromatography and RP-HPLC system to be isolated and purified and obtained 1. The HR-ESI-MS and NMR spectrometer were used to measure the accuracy molecular weights and determine the chemical structure of 1. In conclusion, we isolated and purified compound 1 (15.4 mg) and determined its chemical structure. [ABSTRACT FROM AUTHOR]

Introduction: Pancreatic cancer (PC) is a particularly aggressive malignancy with limited therapeutic options. The search for innovative treatments has focused on traditional Chinese medicine, specifically epimedium. This research investigates epimedium's active ingredients, potential targets, and underlying mechanisms in treating PC. Methods: High-performance liquid chromatography (HPLC) was used to quantify the active components of epimedium and HPLC-Q-TOF-MS was employed for qualitative identification. Potential targets of epimedium's active ingredients were identified using the TCMSP, ETCM, CTD, and Swiss Target Prediction databases. Potential PC-related targets were sourced from DisGeNET, GeneCards, and OMIM databases. A Venn diagram was utilized to identify overlapping PCrelated and epimedium targets. Core targets and pathways were elucidated through protein-protein interaction (PPI) network analysis, Gene Ontology (GO) assessments, and Reactome pathway enrichment analyses. Molecular docking techniques investigated interactions between active compounds and these targets. The expression and prognostic implications of target genes were evaluated using GEPIA2 and the Human Protein Atlas (HPA) databases. In vitro studies assessed the impact of epimedium extract (EPE) on Panc-1 cell viability, and Western blot analysis examined the expression levels of key targets. Results: Network pharmacological indicate that epimedium econtains active components such as baohuoside I, icariin, hyperoside, and epimedin B, which have potential therapeutic effects against PC. In vitro assays confirmed that EPE significantly reduced the viability of Panc-1 cells. Western blot analysis revealed a considerable decrease in the expression of key targets in EPE-treated cells, including AKT1, EGFR, p-EGFR, JUN, BCL2, IL6, and SRC. The R-HSA-1280215: Interleukin-4 and Interleukin-13 signaling pathways involving these genes were identified as potential therapeutic targets. Discussion: Epimedium holds promise as a candidate for treating PC. The modulation of interleukin-4 and interleukin-13 signaling pathways could be a pivotal mechanism by which epimedium impedes tumor development. Further research is warranted to validate these findings and explore the clinical applicability of epimedium in PC treatment. [ABSTRACT FROM AUTHOR]

Epimedium brevicornu Maxim. is a herbal plant with various therapeutic effects, and its aboveground tissues contain flavonol compounds such as icaritin that can be used to produce new drugs for the treatment of advanced liver cancer. Previous studies have shown that ultraviolet-B (UV-B, 280–315 nm) stress can increase the levels of flavonoid substances in plants. In the current study, we observed the microstructure of E. brevicornu leaves after 0, 5, 10, 15, and 20 d of UV-B radiation (60 μw·cm−2) and quality formation mechanism of E. brevicornu leaves after 0, 10, and 20 d of UV-B radiation by LC‒ESI‒MS/MS. The contents of flavonols such as icariside I, wushanicaritin, icaritin, and kumatakenin were significantly upregulated after 10 d of radiation. The results indicated that UV-B radiation for 10 d inhibited the morphological development of E. brevicornu but increased the content of active medicinal components, providing a positive strategy for epimedium quality improvement. [ABSTRACT FROM AUTHOR]

Epimedium sagittatum (Sieb. et Zucc.) Maxim. (ESM) which accumulates several principal flavonoid compounds including epimedin A, B, C and icariin, is extensively utilized in traditional herbs for sexual dysfunction, osteoporosis etc. In China, ESM has a wealth of wild plant resources and characterized by significant variability in medicinal compounds accumulation. Understanding the diversity of ESMs can lead to better utilization of these plant resources. In this study, we integrated the metabolomic and transcriptomic analysis of three ESMs that originated in Anhui, Hubei and Jiangxi in China. Results showed that the flavonoid biosynthesis as well as the related gene expression in these ESMs revealed substantial differences. For example, the epimedin A, B, C and icariin as well as some related gene expression in ESMs from Anhui are significantly lower than those of in others. These results suggested that the ESMs from wild population without quality checkout may not be suitable for directly use as the materials for preparation of Chinese medicine and ESMs with different accumulation of metabolites could be used for distinct applications. [ABSTRACT FROM AUTHOR]

The untargeted metabolomics-based molecular networking approach combined with multivariate analysis, proves to be an effective strategy for distinguishing raw materials in herbal medicine according to specific criteria. It exhibits the correlations between chemical constituents and the geographical habitats of plants, providing a valuable tool for ensuring quality control in mass production within the industry. In this study, we conducted a comprehensive investigation of the chemical compositions of Epimedium koreanum Nakai and performed comparative analyses on four extracts collected from distinct regions in South Korea using untargeted metabolomics tools. Through the comprehensive use of UPLC-QTOF/MS analysis and advanced statistical techniques, we elucidated the chemical composition, leading to the identification of key chemical markers. Additionally, the molecular networking analysis revealed distinct clusters of flavonoids and phenolic acids, highlighting the influence of regional factors on the metabolite profiles. These findings offer a promising avenue for enhancing quality control and traceability in the herbal medicine industry, underscoring the important role of geographical variation in the chemical profiles of herbal products. [ABSTRACT FROM AUTHOR]

Osteoporosis is a global health challenge characterized by bone loss and microstructure deterioration, which urgently requires the development of safer and more effective treatments due to the significant adverse effects and limitations of existing drugs for long-term treatment. Traditional Chinese medicine, like Epimedium, offers fewer side effects and has been used to treat osteoporosis, yet its active compounds and pharmacological mechanisms remain unclear. In this study, 65 potential active compounds, 258 potential target proteins, and 488 pathways of Epimedium were identified through network pharmacology analysis. Further network analysis and review of the literature identified six potential active compounds and HIF-1α for subsequent experimental validation. In vitro experiments confirmed that 2″-O-RhamnosylIcariside II is the most effective compound among the six potential active compounds. It can promote osteoblast differentiation, bind with HIF-1α, and inhibit both HIF-1α gene and protein expression, as well as enhance COL1A1 protein expression under hypoxic conditions. In vivo experiments demonstrated its ability to improve bone microstructures and reduce bone loss by decreasing bone marrow adipose tissue, enhancing bone formation, and suppressing HIF-1α protein expression. This study is the first to describe the therapeutic effects of 2-O-RhamnosylIcariside II on osteoporosis, which was done, specifically, through a mechanism that targets and inhibits HIF-1α. This study provides a scientific basis for the clinical application of Epimedium and offers a new candidate drug for the treatment of osteoporosis. Additionally, it provides new evidence supporting HIF-1α as a therapeutic target for osteoporosis. [ABSTRACT FROM AUTHOR]

Hyperactivation of the cyclic‐GMP‐AMP synthase (cGAS)–stimulator of interferon genes (STING) signalling pathway has been shown to be associated with the development of a variety of inflammatory diseases, and the discovery of an inhibitor of the cGAS‐STING signalling pathway holds great promise in the therapeutic interventions. Epimedium flavonoid (EF), a major active ingredient isolated from the medicinal plant Epimedium, has been reported to have good anti‐inflammatory activity, but its exact mechanism of action remains unclear. In the present study, we found that EF in mouse bone marrow‐derived macrophages (BMDMs), THP‐1 (Tohoku Hospital Pediatrics‐1) as well as in human peripheral blood mononuclear cells (hPBMC) inhibited the activation of the cGAS‐STING signalling pathway, which subsequently led to a decrease in the expression of type I interferon (IFN‐β, CXCL10 and ISG15) and pro‐inflammatory cytokines (IL‐6 and TNF‐α). Mechanistically, EF does not affect STING oligomerization, but inhibits the formation of functional STING signalosome by attenuating the interaction of interferon regulatory factor 3 (IRF3) with STING and TANK‐binding kinase 1 (TBK1). Importantly, in vivo experiments, EF has shown promising therapeutic effects on inflammatory diseases mediated by the cGAS‐STING pathway, which include the agonist model induced by DMXAA stimulation, the autoimmune inflammatory disease model induced by three prime repair exonuclease 1 (Trex1) deficiency, and the non‐alcoholic steatohepatitis (NASH) model induced by a pathogenic amino acid and choline deficiency diet (MCD). To summarize, our study suggests that EF is a potent potential inhibitor component of the cGAS‐STING signalling pathway for the treatment of inflammatory diseases mediated by the cGAS‐STING signalling pathway. [ABSTRACT FROM AUTHOR]

Phosphorus, a crucial macronutrient essential for plant growth and development. Due to widespread phosphorus deficiency in soils, phosphorus deficiency stress has become one of the major abiotic stresses that plants encounter. Despite the evolution of adaptive mechanisms in plants to address phosphorus deficiency, the specific strategies employed by species such as Epimedium pubescens remain elusive. Therefore, this study observed the changes in the growth, physiological reponses, and active components accumulation in E. pubescensunder phosphorus deficiency treatment, and integrated transcriptome and miRNA analysis, so as to offer comprehensive insights into the adaptive mechanisms employed by E. pubescens in response to phosphorus deficiency across various stages of phosphorus treatment. Remarkably, our findings indicate that phosphorus deficiency induces root growth stimulation in E. pubescens, while concurrently inhibiting the growth of leaves, which are of medicinal value. Surprisingly, this stressful condition results in an augmented accumulation of active components in the leaves. During the early stages (30 days), leaves respond by upregulating genes associated with carbon metabolism, flavonoid biosynthesis, and hormone signaling. This adaptive response facilitates energy production, ROS scavenging, and morphological adjustments to cope with short-term phosphorus deficiency and sustain its growth. As time progresses (90 days), the expression of genes related to phosphorus cycling and recycling in leaves is upregulated, and transcriptional and post-transcriptional regulation (miRNA regulation and protein modification) is enhanced. Simultaneously, plant growth is further suppressed, and it gradually begins to discard and decompose leaves to resist the challenges of long-term phosphorus deficiency stress and sustain survival. In conclusion, our study deeply and comprehensively reveals adaptive strategies utilized by E. pubescens in response to phosphorus deficiency, demonstrating its resilience and thriving potential under stressful conditions. Furthermore, it provides valuable information on potential target genes for the cultivation of E. pubescens genotypes tolerant to low phosphorus. [ABSTRACT FROM AUTHOR]

Epimedium is an essential genus of homologous plants used as medicine and food, which has various pharmacological effects and great utilization value in the market. Currently, research into the quality of Epimedium focuses mainly on species and region identification. However, the harvesting period also influences the quality of Epimedium; this aspect requires further study. In this paper, a systematic method is developed based on high-performance liquid chromatography (HPLC) fingerprint analysis, chemometrics, and network pharmacology methods to compare the quality of Epimedium from two harvest periods. A method is developed using liquid chromatography–mass spectrometry (LC-MS) to identify fingerprint peaks. Chemical composition analysis is performed using cluster analysis and orthogonal partial least squares discriminant analysis (OPLS-DA). Ultimately, network pharmacology analysis is employed to forecast the potential effects of compounds associated with standard chromatographic peaks. The fingerprint peaks were identified through LC-MS and corroborated with references. Subsequently, chemometric analysis revealed a distinct division between the HPLC fingerprints of samples from the two harvest periods. This was accomplished by employing cluster analysis and OPLS-DA. Additionally, utilizing the variable impact projection (VIP) obtained from OPLS-DA, a total of seven compounds exhibiting quality discrepancies were identified. Lastly, the network pharmacology analysis indicated that compounds corresponding to typical chromatographic peaks demonstrate therapeutic effects on osteoporosis. Moreover, primary bioactive compounds are identified through degree value screening. This approach is powerful for the quality assessment of Epimedium from different harvesting periods and can also be extensively applied for the quality control of other herbal materials. [ABSTRACT FROM AUTHOR]

Epimedium has been used for functional foods with many beneficial functions to human health. Wushanicaritin is one of the most important chemicals int Epimedium. This study investigated the neuroprotective effects of wushanicaritin and potential underlying mechanisms. The results demonstrated that wushanicaritin possessed superior intercellular antioxidant activity compared to icaritin. Wushanicaritin, with an EC50 value of 3.87 μM, showed better neuroprotective effect than quercetin, a promising neuroprotection agent. Wushanicaritin significantly reversed lactate dehydrogenase release, reactive oxygen species generation, cell apoptosis, and mRNA expression related to cell apoptosis and oxidative defense, in glutamate-induced PC-12 cells. Wushanicaritin could also maintain the enzymatic antioxidant defense system and mitochondrial function. The suppression of caspase-3 activation and amelioration of mitochondrial membrane potential loss and nucleus morphology changes were involved in the antiapoptotic effect of wushanicaritin. These findings suggested that wushanicaritin possesses excellent intercellular antioxidant and neuroprotective activities, showing potential promise in functional foods. [ABSTRACT FROM AUTHOR]

Epimedium koreanum is a perennial herb of the Berberidaceae family, which is a traditional tonic in Chinese medicine. Seed germination of E. koreanum is difficult. Dormancy is an intrinsic factor that affects seed germination. Elucidating the molecular mechanism of seed dormancy and the lifting process of E. koreanum is of great significance for the breeding, conservation, and utilization of E. koreanum. Previous studies have concluded that E. koreanum seed dormancy breakage requires warm-temperature stratification followed by low-temperature stratification treatments. Therefore, we performed transcriptome sequencing using freshly harvested, untreated seeds (NS), seeds that developed a cotyledonary embryo after 90 d of constant-temperature stratification at 15 °C (CS), and seeds that broke dormancy by 90 d of stratification at 15 °C and 60 d of stratification at 5 °C (ND) in order to find the responsive genes and regulatory genes that regulate dormancy. A total of 92,867 genes with differential expression were identified. GO enrichment analysis highlighted redox processes, as well as structural components of the nucleus and ribosomes. KEGG enrichment analysis revealed a significant enrichment of phytohormone signaling pathways, which play a crucial role in seed dormancy release. Additionally, protein–protein interactions (PPIs) were predicted with starch and sucrose metabolic pathways. This study introduces a novel concept for a more profound comprehension of the molecular regulatory mechanism of E. koreanum and lays a theoretical foundation for the screening of E. koreanum candidate genes. [ABSTRACT FROM AUTHOR]

Epimedium koreanum is a traditional Chinese tonic herb. Its main medicinal components are secondary metabolites such as flavonoids and flavonol glycosides, but the biosynthetic mechanism is still unclear. Moisture conditions are a key environmental factor affecting E. koreanum medicinal components during harvesting. Different stages of E. koreanum under natural conditions after rainfall were selected to study changes in physiological properties, herb quality, and transcriptome. Malondialdehyde (MDA) content increased significantly in the D3 stage after rainfall, and protective enzyme levels also rose. Additionally, the flavonol glycoside content was relatively high. We sequenced the transcriptomes of D1, D3, and D9 (R) and identified differentially expressed genes (DEGs) related to flavonoid synthesis. This analysis allowed us to predict the roadmap and key genes involved in flavonoid biosynthesis for E. koreanum. These results suggest that the E. koreanum quality can be enhanced by natural drought conditions in the soil after precipitation during harvest. The harvesting period of E. koreanum is optimal when soil moisture naturally dries to a relative water content of 26% after precipitation. These conditions help E. koreanum tolerate a certain level of water scarcity, resulting in increased expression of flavonoid-related genes and ultimately enhancing the quality of the herb. [ABSTRACT FROM AUTHOR]

The flowering and fruiting phenology and pollen activity of 9 species of Epimedium were observed, the results showed that the flowering period was distributed from early March to late May, with a flowering rate of 6.5%-46.0%, and the fruit period was distributed from midMarch to early June, with a fruiting rate of 8%-36%. There were also differences in the time and length of flowering and fruiting period among different cultivars of Epimedium, and the duration of full flowering period was different. In both large flower group and small flower group, TTC method found that the strongest pollen activity period was half blooming period. [ABSTRACT FROM AUTHOR]

Objective Based on network pharmacology and WGCNA methods, to explore the potential targets of Epimedium in the treatment of prostate cancer, in order to provide a theoretical basis for the clinical treatment of prostate cancer. Methods The active components of Epimedium and their corresponding target genes were obtained by TCMSP, ETCM database and 2020 edition of Pharmacopoeia. R language was used to analyze the difference of data set GSE46602. WGCNA screened the key genes of prostate cancer and obtained the target genes of Epimedium-prostate cancer intersection. GO and KEGG pathway enrichment analysis were further performed. STRING and Cytoscape software were used to construct protein interaction network and drug active ingredient-target-pathway-disease network. UALCAN website and GEPIA database were used to verify the correlation between key genes and Gleason grade. Results There were 31 effective active components of Epimedium, 228 corresponding target genes, and 9 potential targets of Epimedium against prostate cancer. GO analysis showed that disease intersection genes were enriched in gland development, VEGF-A complex and other processes, and KEGG pathway enrichment showed that they were mainly enriched in chemical carcinogenesis-receptor activation, VEGF signaling pathway and other pathways. Drug-active ingredient-common target-pathway-disease network analysis Epimedium core activity became quercetin, luteolin and kaempferol; UALCAN analysis showed that the expression of intersection genes was significantly correlated with Gleason grade. GEPIA database verification showed that the expression of VEGFA, PGR, AKR1B1 and GSTM1 genes was decreased in prostate cancer tissues. Conclusion VEGFA, PGR, AKR1B1 and GSTM1 genes are the main targets of Epimedium anti-prostate cancer. The core activity of Epimedium in the treatment of prostate cancer is quercetin, luteolin and kaempferol, which may play a role in the treatment of prostate cancer through VEGF signaling pathway. [ABSTRACT FROM AUTHOR]

At different time scales, a species will experience diverse distribution changes. For Epimedium brevicornum Maxim, the phenomenon is obvious, but the understanding of the spatial dynamics of E. brevicornum under distinct time scales is poor. In this study, we modeled the potential distribution for E. brevicornum for five time scales, 1970–1979, 1980–1989, 1990–1999, 2000–2009, and 2010–2019, with different occurrence data, and the Kuenm package was used to optimize the parameter combination. Then, SDM tools and a Venn diagram were utilized to simulate the changes in highly suitable areas and spatial dynamics, respectively. Comprehensive results show that temperature seasonality (BIO4, 37.54%) has the greatest effect on the distribution of E. brevicornum, followed by minimum temperature (TMIN, 21.42%). The areas of distribution for E. brevicornum are 35.06 × 105 km2, 25.7 × 105 km2, 67.64 × 105 km2, 27.29 × 105 km2, and 9.87× 105 km2, which are mainly concentrated in Gansu, Shaanxi, Shanxi, and Henan, respectively. In addition, the largest regions for expansion, stability, and contraction under various time scales are 5.6 × 105 km2, 3.54 × 105 km2, and 3.47 × 105 km2, respectively. These changes indicate that approximately 7.96% of the regions are highly stable, and three critical counties, Wanyuan, Chenggu, and Hechuan, and Xixiang, have become significant areas for migration. Overall, our results indicate that there are different spatial distribution patterns and dynamics for E. brevicornum for different time scales. Given these results, this study also proposes comprehensive strategies for the conservation and management of E. brevicornum, which will further improve the current resource utilization status. [ABSTRACT FROM AUTHOR]

BACKGROUND: In clinical practice, Cibotium barometz and Epimedium have shown significant efficacy in the treatment of rheumatoid arthritis, but the complex active ingredients contained in the two have an unclear mechanism of action at the molecular level for the treatment of rheumatoid arthritis. OBJECTIVE: Based on network pharmacology and molecular docking technology, to establish a collagen-induced arthritis model and to verify the potential targets and pathways of Cibotium barometz and Epimedium in the treatment of rheumatoid arthritis, providing reliable experimental evidence for the use of clinical formulas with Cibotium barometz and Epimedium as the main components. METHODS: Utilizing traditional Chinese medicine research platforms, traditional Chinese medicine encyclopedias, and databases of traditional Chinese medicine and chemical components from the Shanghai Institute of Organic, effective ingredients were retrieved and identified. 3D molecular formulas were obtained from the PubChem platform and target predictions were made using PharmMapper and SwissTargetPrediction. Disease targets for rheumatoid arthritis were obtained from gene databases such as DrugBank, GeneCards, and OMIM. The intersections of targets and Cibotium barometz and Epimedium were plotted using VENNY 2.1 after calibration with the Uniport database. A protein-protein interaction network graph was constructed using the STRING platform. Gene Ontology function analysis and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed using the Metascape platform for data visualization. A four-layered network model of traditional Chinese medicine, ingredients, targets, diseases, and pathways was constructed using Cytoscape 3.9.0. The main effective ingredients were docked with core targets using AutoDock-Vina software to explore the best binding targets. A type II collagen+adjuvant-induced arthritis rat model was established, and the effects of Cibotium barometz and Epimedium on relevant pathway targets and inflammatory cell factors were observed after 21 days of intervention. RESULTS AND CONCLUSION: A total of 28 active ingredients from Cibotium barometz and Epimedium were selected, yielding 288 intersection targets for rheumatoid arthritis. The main ingredients included isobavachalcone, cibotium, and epimedium. The main targets included protein kinase 1 for serine/ threonine (AKT1), tumor necrosis factor, and vascular endothelial growth factor A. Gene ontology analysis yielded 2 232 biological processes, mainly related to serine protein phosphorylation, positive regulation of serine/threonine protein kinase, and reactive oxygen metabolism. Kyoto Encyclopedia of Genes and Genomes enrichment analysis yielded 202 pathways, mainly involving the PI3K/AKT signaling pathway and epidermal growth factor receptor signaling pathway, which may exert therapeutic effects by regulating synovial cell apoptosis and proliferation and suppressing inflammatory factors. Molecular docking results showed the strongest binding activity and stable structure of Cibotium barometz and Epimedium with AKT1 and estrogen receptor transcription factor 1, which was closely related to apoptosis and proliferation and inflammatory signaling pathways such as PI3K/AKT. Cibotium barometz and Epimedium reduced the expression of interleukin-1β, interleukin-6, and tumor necrosis factor-α in the serum of collagen-induced arthritis rat models. Cibotium barometz and Epimedium reduced the expression of p-PI3K, p-AKT, and p-FOXO1 in the synovium of collagen-induced arthritis rat models. The results indicate that the combination of Cibotium barometz and Epimedium may exert therapeutic effects by inhibiting the proliferation of synovial cells and suppressing the expression of inflammatory factors via the PI3K/AKT/FOXO1 signaling pathway. This may be closely related to the occurrence of inflammation and bone destruction in rheumatoid arthritis, and provides a reference for the rational use and development of new drugs in clinical practice. [ABSTRACT FROM AUTHOR]

Cyclophosphamide (CTX) is a broad-spectrum alkylated antitumor drug. It is clinically used in the treatment of a variety of cancers, and renal toxicity is one of the adverse reactions after long-term or repeated use, which not only limits the therapeutic effect of CTX, but also increases the probability of kidney lesions. The total flavonoids of Epimedium stem and leaf (EBF) and Icariin (ICA) are the main medicinal components of Epimedium, and ICA is one of the main active substances in EBF. Modern pharmacological studies have shown that EBF has a variety of biological activities such as improving osteoporosis, promoting cell proliferation, antioxidant and anti-inflammatory properties, etc. However, few studies have been conducted on the nephrotoxicity caused by optimized CTX extraction, and protein-ligand binding has not been involved. This research, through the response surface optimization extraction of EBF, obtained the best extraction conditions: ethanol concentration was 60%, solid-liquid ratio of 25:1, ultrasonic time was about 25 min. Combined with mass spectrometry (MS) analysis, EBF contained ICA, ichopidin A, ichopidin B, ichopidin C, and other components. In this study, we adopted a computational chemistry method called molecular docking, and the results show that Icariin was well bound to the antioxidant target proteins KEAP1 and NRF2, and the anti-inflammatory target proteins COX-2 and NF-κB, with free binding energies of −9.8 kcal/mol, −11.0 kcal/mol, −10.0 kcal/mol, and −8.1 kcal/mol, respectively. To study the protective effect of EBF on the nephrotoxicity of CTX, 40 male Kunming mice (weight 18 ± 22) were injected with CTX (80 mg/kg) for 7 days to establish the nephrotoxicity model and were treated with EBF (50 mg/kg, 100 mg/kg) for 8 days by gavage. After CTX administration, MDA, BUN, Cre, and IL-6 levels in serum increased, MDA increased in kidney, GPT/ALT and IL-6 increased in liver, and IL-6 increased in spleen and was significant ((p < 0.05 or (p < 0.01)). Histopathological observation showed that renal cortex glomerular atrophy necrosis, medullary inflammatory cell infiltration, and other lesions. After administration of EBF, CTX-induced increase in serum level of related indexes was reduced, and MDA in kidney, GPT/ALT and IL-6 in liver, and IL-6 in spleen were increased. At the same time, histopathological findings showed that the necrosis of medullary and corticorenal tubular epithelium was relieved at EBF (50 mg/kg) dose compared with the CTX group, and the glomerular tubular necrosis gradually became normal at EBF (100 mg/kg) dose. Western blot analysis of Keap1 and Nrf2 protein expression in kidney tissue showed that compared with model CTX group, the drug administration group could alleviate the high expression of Keap1 protein and low expression of Nrf2 protein in kidney tissue. Conclusion: After the optimal extraction of total flavonoids from the stems and leaves of Epimedium, the molecular docking technique combined with animal experiments suggested that the effective component of the total flavonoids of Epimedium might activate the Keap1-Nrf2 signaling pathway after treatment to reduce the inflammation and oxidative stress of kidney tissue, so as to reduce kidney damage and improve kidney function. Therefore, EBF may become a new natural protective agent for CTX chemotherapy in the future. [ABSTRACT FROM AUTHOR]

Epimedium (EM) and Psoraleae Fructus (PF) are a traditional herb combination often used as a fixed form to treat osteoporosis disease in the clinic. However, the intricate interactions of this pair remain unknown. In our study, we undertook a comprehensive examination of their compatibility behaviors. Concurrently, a precise and sensitive quantitation method was successfully developed and validated using liquid chromatography‐tandem mass spectrometry for the determination of 12 components. This method was applied in analyzing herbal extracts and biological samples (both in the portal vein and systemic plasma), which was also used to study the pharmacokinetics of the herb pair. The results indicated that the combination of EM and PF enhanced the dissolution of chemical components from PF in extracts, but it had a negligible influence on the contents of the components from EM. On the contrary, the in vivo exposure of the lowly exposed EM flavonoids significantly increased following the combination of EM and PF, whereas the highly exposed psoralen and isopsoralen were greatly reduced. These interactions might be crucial for the synergy and toxicity reduction of the herbal pair in disease treatment, which pave the way for further exploration into the clinical application and pharmacological mechanisms of EM and PF. [ABSTRACT FROM AUTHOR]

The epimedium plant (Epimedium brevicornum Maxim) has activity as an aphrodisiac derived from a flavonoid compound, namely icariin. Icariin has low solubility and bioavailability. The utilization of icariin using the SNEDDS (Self Nanoemulsifying Drug Delivery System) method is expected to increase the solubility and bioavailability of icariin. This study aims to determine the optimum formula, characteristics, physical properties, and aphrodisiac activity of SNEDDS icariin. The optimum formula used is tween 80 (75%): PEG 400 (12.5%) and cucut fish oil (12.5%). The characteristics of SNEDDS icariin obtained were droplet size with an average of 15.63±0.058 nm, PI 0.144±0.062, zeta potential -22.67±2.06 mV, emulsification time 12.30 seconds, and transmittance 97.2%. The physical test of SNEDDS icariin produced in the form of a clear preparation in yellow color, pH 6.52, the viscosity of 120 cps, as well as the SNEDDS icariin dissolution in aqueous media in the 60th minute was 75.40% colluded. SNEDDS icariin dose 50 mg/KgBW has a better aphrodisiac effect than pure icariin 100 mg/kgBW. [ABSTRACT FROM AUTHOR]

Abstract Osteoarthritis (OA) is a common chronic degenerative joint disease in clinical practice with a high prevalence, especially in the elderly. Traditional Chinese Medicine (TCM) believes that OA belongs to the category of “Bi syndrome” and the “bone Bi syndrome”. The etiology and pathogenesis lie in the deficiency of the liver and kidney, the deficiency of Qi and blood, and external exposure to wind, cold, and dampness. Epimedium is a yang-reinforcing herb in TCM, which can tonify the liver and kidney, strengthen muscles and bones, dispel wind, cold and dampness, and can treat both the symptoms and the root cause of “bone Bi syndrome”. In addition, Epimedium contains a large number of ingredients. Through modern science and technology, more than 270 compounds have been found in Epimedium, among which flavonoids are the main active ingredients. Therefore, our study will review the effects and mechanisms of genus Epimedium in treating OA from two aspects: (1) Introduction of Epimedium and its main active ingredients; (2) Effects of Epimedium and its active ingredients in treating OA and relevant signaling pathways, in order to provide more ideas for OA treatment.

Epimedium koreanum Nakai, a well-known traditional Chinese medicinal herb, has been widely used to treat osteoporosis and sexual dysfunction for thousands of years. However, due to the decreasing population of East Asian natural resources, yearly output of Epimedium crude herb has been in low supply year by year. In this study, an unusual variety of E. koreanum was discovered in Dunhua, Jilin Province, the northernmost area where this variety was found containing 6 individuals, with three branches that had 27 leaflets, which is much more than the typical leaflet number of 9. Firstly, the novel E. koreanum varety was identified using DNA barcodes. Then, 1171 differentially expressed genes (DEGs) were discovered through parallel RNA-seq analysis between the newly discovered variety and wild type (WT) E. koreanum plant. Furthermore, the results of bioinformatics investigation revealed that 914 positively and 619 negatively correlated genes associated with the number of leaflets. Additionally, based on RNA-Seq and qRT-PCR analysis, two homologous hub TCP genes, which were commonly implicated in plant leaf development, and shown to be up regulated and down regulated in the discovered newly variety, respectively. Thus, our study discovered a novel wild resource for leaf yield rewarding medicinal Epimedium plant breeding, provided insights into the relationship between plant compound leaf formation and gene expression of TCPs transcription factors and other gene candidates, providing bases for creating high yield cultivated Epimedium variety by using further molecular selection and breeding techniques in the future. [ABSTRACT FROM AUTHOR]

East Asia is the richest region of plant biodiversity in the northern temperate zone, and its radiation provides key insights for understanding rapid speciation, including evolutionary patterns and processes. However, it is challenging to investigate the recent evolutionary radiation among plants because of the lack of genetic divergence, phenotypic convergence, and interspecific gene flow. Epimedium sect. Diphyllon is a rarely studied plant lineage endemic to East Asia, especially highly diversified in its southern part. In this study, we report a robust phylogenomic analysis based on genotyping-by-sequencing data of this lineage. The results revealed a clear biogeographic pattern for Epimedium sect. Diphyllon with recognition into two major clades corresponding to the Sino-- Himalayan and Sino--Japanese subkingdoms of East Asian Flora and rapid diversification of the extant species dated to the Pleistocene. Evolutionary radiation of Epimedium sect. Diphyllon is characterized by recent and predominant parallel evolution and atavism between the two subkingdom regions, with extensive reticulating hybridization within each region during the course of diversification in southern East Asia. A parallel-atavism-introgression hypothesis is referred to in explaining the radiation of plant diversity in southern East Asia, which represents a potential model for the rapid diversification of plants under global climate cooling in the late Tertiary. Our study advances our understanding of the evolutionary processes of plant radiation in East Asia as well as in other biodiversity hotspot regions. [ABSTRACT FROM AUTHOR]

BACKGROUND: With the aging of society, the incidence rate of osteoporosis in many countries is increasing year by year. At present, the cause of osteoporosis is not clear and there is no effective cure for the disease. OBJECTIVE: To summarize the relevant literature at home and abroad, and sum up the research on the signaling pathway related to the regulation of bone marrow mesenchymal stem cell differentiation by Epimedium, in order to further understand the pathogenesis of osteoporosis and improve new ideas for the treatment of osteoporosis. METHODS: CNKI, Wanfang, and VIP databases were searched with the Chinese search terms “Epimedium; osteogenic differentiation; bone marrow mesenchymal stem cells; osteoporosis; signal pathway; Wnt/β-catenin; BMP/Runx2/Osz; MAPK”. MEDLINE and PubMed databases were retrieved with the English search terms “Epimedium; osteogenic differentiation; bone marrow mesochemical stem cells; osteoporosis; signal path; Wnt/β-catenin; BMP/Runx2/Osz; MAPK”. To screen the research articles related to Epimedium in regulating bone marrow mesenchymal stem cell differentiation in the treatment of osteoporosis, a total of 61 articles were included according to the inclusion and exclusion criteria. RESULTS AND CONCLUSION: (1) Epimedium and bone marrow mesenchymal stem cells play an important role in the occurrence of osteoporosis. (2) Most studies have found that Epimedium plays a role in the treatment of osteoporosis mainly through signaling pathways such as Wnt/β-catenin, Notch, BMP/Runx2/ Osz and MAPK to regulate bone marrow mesenchymal stem cells, so as to affect the dynamic balance between osteoclasts and osteoblasts and achieve the best state of maintaining bone homeostasis. Therefore, in-depth study of Epimedium on bone marrow mesenchymal stem cells in the future may improve the potential value of treating osteoporosis. [ABSTRACT FROM AUTHOR]

Epimedium is a classical Chinese herbal medicine, which has been used extensively to treat various diseases, such as sexual dysfunction, osteoporosis, cancer, rheumatoid arthritis, and brain diseases. Flavonoids, such as icariin, baohuoside I, icaritin, and epimedin C, are the main active ingredients with diverse pharmacological activities. Currently, most Epimedium flavonoids are extracted from Epimedium plants, but this method cannot meet the increasing market demand. Biotransformation strategies promised huge potential for increasing the contents of high-value Epimedium flavonoids, which would promote the full use of the Epimedium herb. Complete biosynthesis of major Epimedium flavonoids by microbial cell factories would enable industrial-scale production of Epimedium flavonoids. This review summarizes the structures, pharmacological activities, and biosynthesis pathways in the Epimedium plant, as well as the extraction methods of major Epimedium flavonoids, and advancements in the biotransformation and complete microbial synthesis of Epimedium flavonoids, which would provide valuable insights for future studies on Epimedium herb usage and the production of Epimedium flavonoids. [ABSTRACT FROM AUTHOR]

Abstract Background Leaves are the main medicinal organ in Epimedium herbs, and leaf flavonoid content is an important criterion of Epimedium herbs. However, the underlying genes that regulate leaf size and flavonoid content are unclear, which limits the use of breeding for Epimedium development. This study focuses on QTL mapping of flavonoid and leaf-size related traits in Epimedium. Results We constructed the first high-density genetic map (HDGM) using 109 F1 hybrids of Epimedium leptorrhizum and Epimedium sagittatum over three years (2019–2021). Using 5,271 single nucleotide polymorphism (SNP) markers, an HDGM with an overall distance of 2,366.07 cM and a mean gap of 0.612 cM was generated by utilizing genotyping by sequencing (GBS) technology. Every year for three years, 46 stable quantitative trait loci (QTLs) for leaf size and flavonoid contents were discovered, including 31 stable loci for Epimedin C (EC), one stable locus for total flavone content (TFC), 12 stable loci for leaf length (LL), and two stable loci for leaf area (LA). For flavonoid content and leaf size, the phenotypic variance explained for these loci varied between 4.00 and 16.80% and 14.95 and 17.34%, respectively. Conclusions Forty-six stable QTLs for leaf size and flavonoid content traits were repeatedly detected over three years. The HDGM and stable QTLs are laying the basis for breeding and gene investigation in Epimedium and will contribute to accelerating the identification of desirable genotypes for Epimedium breeding.

Objective(s): Cardiovascular diseases are widespread across the globe, and heart failure (HF) accounts for the majority of heart-associated deaths. Target-based drug therapy is much needed for the management of heart failure. We have designed this study to evaluate icariin for its cardioprotective activity in the isoproterenol (ISO) induced postinfarction model. We have randomly distributed Wistar rats into seven groups, i.e., vehicle control; isoproterenol-treated; icariin per se; sildenafil per se; ISO + icariin 5; ISO + icariin 10; and ISO + sildenafil groups. ISO (85 mg/kg, subcutaneous) was administered at 24 hr for two consecutive days to produce cardiac injury, followed by icariin administration at 5 mg/kg and 10 mg/kg orally for 56 days.Materials and Methods: Rats were subjected to hemodynamic measurements biweekly. After 24 hr of the completion of dosing, animals were sacrificed, and markers for oxidative stress, fibrosis, inflammation, and cell death were measured. Transmission electron microscopy (TEM), histopathology, and MT staining of cardiac tissue were also done to assess the pathological and fibrotic architectural damage. Results: A significant decline in hemodynamics and an antioxidant collapse were found in ISO-intoxicated rats. Alterations in the levels of cyclic guanosine monophosphate (cGMP), interleukin-10 (IL-10), Tumor necrosis factor (TNF-α), and brain natriuretic peptide (BNP) were also observed in serum. Up-regulation of caspase-3, nuclear factor (NF-ĸB), and decline in expression of nuclear factor (NrF-2) contribute to cardiac damage. The treatment with icariin and sildenafil considerably reversed the toxic changes toward normal.Conclusion: Increased cGMP and Nrf2 expression and suppressed NF-ĸB-caspase-3 signaling play a pivotal role in icariin-mediated cardioprotection.

Osteoporosis is a global health challenge characterized by bone loss and microstructure deterioration, which urgently requires the development of safer and more effective treatments due to the significant adverse effects and limitations of existing drugs for long-term treatment. Traditional Chinese medicine, like Epimedium, offers fewer side effects and has been used to treat osteoporosis, yet its active compounds and pharmacological mechanisms remain unclear. In this study, 65 potential active compounds, 258 potential target proteins, and 488 pathways of Epimedium were identified through network pharmacology analysis. Further network analysis and review of the literature identified six potential active compounds and HIF-1α for subsequent experimental validation. In vitro experiments confirmed that 2″-O-RhamnosylIcariside II is the most effective compound among the six potential active compounds. It can promote osteoblast differentiation, bind with HIF-1α, and inhibit both HIF-1α gene and protein expression, as well as enhance COL1A1 protein expression under hypoxic conditions. In vivo experiments demonstrated its ability to improve bone microstructures and reduce bone loss by decreasing bone marrow adipose tissue, enhancing bone formation, and suppressing HIF-1α protein expression. This study is the first to describe the therapeutic effects of 2-O-RhamnosylIcariside II on osteoporosis, which was done, specifically, through a mechanism that targets and inhibits HIF-1α. This study provides a scientific basis for the clinical application of Epimedium and offers a new candidate drug for the treatment of osteoporosis. Additionally, it provides new evidence supporting HIF-1α as a therapeutic target for osteoporosis.

Epimedium has been used for functional foods with many beneficial functions to human health. Wushanicaritin is one of the most important chemicals int Epimedium. This study investigated the neuroprotective effects of wushanicaritin and potential underlying mechanisms. The results demonstrated that wushanicaritin possessed superior intercellular antioxidant activity compared to icaritin. Wushanicaritin, with an EC50 value of 3.87 μM, showed better neuroprotective effect than quercetin, a promising neuroprotection agent. Wushanicaritin significantly reversed lactate dehydrogenase release, reactive oxygen species generation, cell apoptosis, and mRNA expression related to cell apoptosis and oxidative defense, in glutamate-induced PC-12 cells. Wushanicaritin could also maintain the enzymatic antioxidant defense system and mitochondrial function. The suppression of caspase-3 activation and amelioration of mitochondrial membrane potential loss and nucleus morphology changes were involved in the antiapoptotic effect of wushanicaritin. These findings suggested that wushanicaritin possesses excellent intercellular antioxidant and neuroprotective activities, showing potential promise in functional foods.

Purpose: This study aims to explore the effects of two endophytes of Epimedium koreanum Nakai on host plant growth and development and medicinal material quality and to promote the growth and development of ingredients derived from Epimedium koreanum Nakai. Methods: The effects on the biomass, photosynthesis parameters, chlorophyll fluorescence parameters, activity of key enzymes, and active components in the process of growth and development in Korea were examined. Results: From the analysis of biomass and photosynthesis data, both the S3 (Diaporthe cotoneastri) and S10 (Ilyonectria cyclaminicola) strains promoted the growth of Epimedium koreanum Nakai. Redundancy analysis (RDA) showed that the activity of S3 and the content of epimedin A were negatively correlated and that the peroxidase (POD) activity was positively correlated with the total flavonoid content. Conclusion: The application of the S3 (Diaporthe cotoneastri) and S10 (Ilyonectria cyclaminicola) strains can significantly increase the biomass and contents of total flavonoids, icariin, epimedin B, and epimedin C, but not epimedin A, in Epimedium koreanum Nakai host plants grown in field conditions. The S10 strain promotes faster growth of Epimedium koreanum Nakai than the S3 strain, and flavonoid 3-hydroxylase (F3H) catalyzes the synthesis of epimedin A and icariin by different pathways using the same substrate. POD plays a key role in total flavonoid synthesis in Epimedium koreanum Nakai. [ABSTRACT FROM AUTHOR]

Epimedium and Plagiorhegma are the representatives of two early-diverging clades in Podophylloideae of Berberidaceae. Flowers are dimerous and trimerous respectively, but their floral development is little known. Here, we used scanning electron microscopy to clarify the structure and development of flower and inflorescence in E pimedium pubescens and P lagiorhegma dubium and compared these with other Berberidaceae to better understand floral evolution within the family. Our results show that the two genera share some significant features. The petal and stamen primordia emerge independently. The carpel is ascidiate from the earliest stages of development. The ovule is anatropous and bitegmic. However, E. pubescens has a paniculate inflorescence, while a lateral floral bud is initiated but aborted in P. dubium. In E. pubescens , both inner sepals and petals are delayed compared with other organs (vs. delay in petal development only for P. dubium). Petals of E. pubescens have a nectariferous spur (vs. no nectariferous tissue for P. dubium). The style of E. pubescens is long with a flat stigma (vs. short with trumpet-shaped stigma for P. dubium). These differences suggest that Epimedium and Plagiorhegma may not be closely related and support placing them separately in two clades of Podophylloideae, complementing results from molecular studies. [ABSTRACT FROM AUTHOR]

Objective： To analyze the effective chemical components and their action targets of epimedium in the treatment of hypothalamus-pituitary-adrenal gland/gonad/thyroid gland axis functional damage by using network pharmacology and molecular docking technology, and to preliminarily clarify its mechanism. Methods The effective chemical components and their corresponding target proteins of epimedium were screened by Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database and Analysis Platform combined with the relevant literatures, and the Uniprot Database was used to standardize the target protein informations to get the corresponding standard gene names; the relevant target genes of hypothalamus-pituitary-adrenal gland/gonad/thyroid gland axis function damage were collected from the GeneCards Database and DisGeNET Database；the network of the relationship between the effective chemical components of the epimedium and their action targets was constructed by Cytascape 3.7.1 Software; the protein-protein interaction (PPI) network diagram of drug-disease of effective chemical components and target proteins of hypothalamus-pituitary-adrenal gland/gonad/thyroid gland axis function damage was constructed by STRING Database. Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genome (KEGG) signaling pathway enrichment analysis were performed by OmicShare Database；molecular simulation docking and visualization were done by Pymol Software and the Autodock Tools Software. Results A total of 27 effective chemical components and 217 corresponding action targets of epimedium, and 465 target genes of hypothalamus-pituitary-adrenal gland/gonad/thyroid gland axis function damage were screened out, of which 62 target genes were closely related to the treatment of hypothalamus-pituitary-adrenal gland/gonad/thyroid gland axis function damage by epimedium.Quercetin，luteolin，kaempferol, and icariin and so on were the key effective chemical components, and the key target proteins were Cysteine protease 3 containing cysteine (Caspase-3), interleukin-6 (IL-6), oligosaccharides (FOS), tumor necrosis factor (TNF), hypoxia inducible factor-1 alpha (HIF1A), vascular endothelial growth factor A (VEGFA), interleukin-1β (IL-1β), estrogen receptor 1 (ESR1) ，recombinant prostaglandin endoperoxide synthase 2 (PTGS2), matric metallopeptidase 9 (MMP-9) ，and so on.The KEGG signaling pathway enrichment analysis results showed that the common targets were mainly concentrated in the pathways related to immune inflammation, hormone regulation, and energy metabolism. The molecular docking results showed that the potential active components of epimedium had a good affinity with IL-6, PTGS2, aldose reductase (AR), and mitogen-activated protein kinase 1 (MAPK1) targets. Conclusion Epimedium may play a potential therapeutic role in the treatment of hypothalamus-pituitary-adrenal gland/gonad/thyroid gland axis function damage in the aspects of anti-inflammatory immunity, hormone regulation, and energy metabolism through multiple targets and pathways. [ABSTRACT FROM AUTHOR]

Objective: Epimedium (EPI) is a common Chinese herb with neuroprotective effects against a variety of central nervous system disorders, especially spinal cord injury (SCI). In this study, we performed network pharmacology and molecular docking analyses to reveal the mechanism underlying EPI treatment of SCI, then validated its efficacy using animal models. Methods: The active ingredients and targets of EPI were screened by Traditional Chinese Medicine Systems Pharmacology (TCMSP) and their targets annotated on the UniProt platform. SCI-related targets were searched from OMIM, TTD, and GeneCards databases. We employed the STRING platform to construct a protein-protein interaction (PPI) network then visualized the results using Cytoscape (3.8.2) software. We also subjected key EPI targets to ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, then docked the main active ingredients with the key targets. Finally, we established an SCI rat model to evaluate efficacy of EPI in treating SCI and validate the effects of different biofunctional modules predicted by network pharmacology. Results: A total of 133 EPI targets were associated with SCI. GO terms and KEGG pathway enrichment results showed that EPI's effect in treating SCI was significantly associated with inflammatory response, oxidative stress and the PI3K/AKT signaling pathway. Molecular docking results indicated that EPI's active ingredients have a high affinity for the key targets. Results from animal experiments revealed that EPI not only markedly improved Basso, Beattie, and Bresnahan scores in SCI rats, but also significantly improved p-PI3K/PI3K and p-AKT/AKT ratio. Moreover, EPI treatment not only mediated a significant decrease in malondialdehyde (MDA) but also increased both superoxide dismutase (SOD), and glutathione (GSH). However, this phenomenon was successfully reversed by LY294002, a PI3K inhibitor. Conclusion: EPI improves behavioral performance in SCI rats through anti-oxidative stress, which may be mediated by activation of the PI3K/AKT signaling pathway. [ABSTRACT FROM AUTHOR]

The evolution and expression of floral traits are responsive to selection pressure from biotic and abiotic factors. Although floral traits significantly vary among environments, the flower remains unchanged. We aimed to understand the adaptation of Epimedium chlorandrum of floral traits to a frequently nocturnally rainy and wet environments and the roles of floral traits in pollination and reproduction. We observed flowering phenology, measured floral characteristics including the number of pollen grains and ovules per flower, measured pollen viability and stigma receptivity, tested the volume and sugar concentration of nectar and conducted flower-visit observations in this species. Different pollination treatments were performed to characterize the breeding system. The inner sepals and highly curved longer spurs of E. chlorandrum jointly formed an umbrella that shielded the anthers and stigma from rain wash and prevented nectar dilution. Epimedium chlorandrum was visited by six species, while Bombus trifasciatus was the only effective pollinator and fed on the nectar. One flower secreted approximately 17.06 µL of nectar with a 29.19 g/100 mL sugar concentration, and the pollination efficiency of B. trifasciatus was positively associated with the nectar sugar concentration. The self- and open-pollination treatments resulted in fewer fertile seeds than the cross-pollination treatment. In contrast, the autonomous self-pollination treatment failed to yield fertile seeds. In summary, pollen limitation caused by harsh weather and pollinator shortage occurred during the pollination process of E. chlorandrum , which was partially alleviated by self-compatibility. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a common chronic degenerative joint disease in clinical practice with a high prevalence, especially in the elderly. Traditional Chinese Medicine (TCM) believes that OA belongs to the category of "Bi syndrome" and the "bone Bi syndrome". The etiology and pathogenesis lie in the deficiency of the liver and kidney, the deficiency of Qi and blood, and external exposure to wind, cold, and dampness. Epimedium is a yang-reinforcing herb in TCM, which can tonify the liver and kidney, strengthen muscles and bones, dispel wind, cold and dampness, and can treat both the symptoms and the root cause of "bone Bi syndrome". In addition, Epimedium contains a large number of ingredients. Through modern science and technology, more than 270 compounds have been found in Epimedium, among which flavonoids are the main active ingredients. Therefore, our study will review the effects and mechanisms of genus Epimedium in treating OA from two aspects: (1) Introduction of Epimedium and its main active ingredients; (2) Effects of Epimedium and its active ingredients in treating OA and relevant signaling pathways, in order to provide more ideas for OA treatment. [ABSTRACT FROM AUTHOR]

BACKGROUND: Segmental bone defects are a challenging orthopedic problem and the existing treatment methods are not effective. Bone tissue engineering techniques have shown great potential in the repair of segmental bone defects; however, the osteogenic properties of artificial scaffolds alone are often insufficient to meet the needs of bone defect repair and the loading of growth factors is expensive and unstable. Chinese medicines are widely available and inexpensive and those with the active ingredients of “tonifying kidney and strengthening bones” have the potential to act as exogenous growth factors. Therefore, the composite scaffolds of Chinese medicines have shown good bone tissue repair effects. OBJECTIVE: To introduce several commonly used bone tissue engineering scaffold materials as well as some representative drugs of tonifying kidney and strengthening bones, such as Rhizome Drynariae, Epimedium, and Eucommia, that are used combined with scaffold materials, and discuss the potential of Chinese medicines with the active ingredients of “tonifying kidney and strengthening bones” in the repair of segmental bone defects using bone tissue engineering scaffolds. METHODS: The first author searched for relevant literature (published from 2007 to 2022) regarding the use of Chinese medicines of “tonifying kidney and strengthening bones” in the repair of segmental bone defects using bone tissue engineering scaffolds in CNKI, WanFang, PubMed, and Web of Science. Search terms included “Chinese medicine, Tonifying kidney, Drynariae, Epimedium, Eucommia, Bone defects, Bone repair, Bone tissue engineering, Scaffold” in Chinese and English. RESULTS AND CONCLUSION: (1) The existing bone tissue engineering scaffold materials include bioceramic materials, medical metal materials, and polymer materials, which can be used in combination to compensate for the performance deficiencies of a single material as per the difference in their properties. (2) Exogenous growth factors combined with bone tissue engineering scaffolds are highly effective in repairing segmental bone defects, but growth factors are unstable and expensive. (3) Modern pharmacology has found that Chinese medicines of tonifying kidney and strengthening bones can significantly promote the osteogenic differentiation of bone marrow mesenchymal stem cells, which can replace the role of growth factors in bone tissue engineering scaffolds. (4) The combination of Chinese medicines of tonifying kidney and strengthening bones and its active ingredients with scaffold materials to produce composite scaffolds has shown unique advantages in the repair of segmental bone defects and has great potential for application. [ABSTRACT FROM AUTHOR]

Background: Kidney-Yang deficiency syndrome (KDS) is a group of diseases related to hypothalamic-pituitary-adrenal (HPA) axis and sexual dysfunction. The folium of Epimedium brevicornu Maxim. (FEB) includes raw and prepared slices, named RFEB and PFEB, respectively. PFEB is traditionally believed to be good for tonifying kidney-Yang and improving sexual dysfunction. However, there are few studies comparing the pharmacological effects of RFEB and PFEB, and their underlying mechanisms. In this study, we aimed to compare the effects and safety of RFEB and PFEB on the HPA axis and sexual function. Additionally, the mechanisms of their roles in relation to the neuroendocrine-immune (NEI) network in the KDS model mice were explored. Methods: Male adult C57BL/6 mice were treated with corticosterone to establish a KDS mouse model, and RFEB and PFEB were administered intragastrically. Corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH), cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), testosterone levels and oxidative damage indexes were measured. The mRNA and protein levels of CRH and ACTH in hypothalamus and pituitary, endothelial nitric oxide synthase (eNOS) and phosphodiesterase 5 (PDE5) in corpus cavernosum were examined. TNFα, IL-6, NF-κB, eNOS and PDE5 were investigated in mouse corpus cavernosum. Results: Our results showed that PFEB was more effective than RFEB in increasing corticosterone-suppressed ACTH levels, enhancing CRH levels and cAMP/cGMP ratio, and reducing oxidative damage. In vivo, PFEB significantly increased eNOS and inhibited PDE5 expression in corpus cavernosum. PFEB showed stronger protective effect on normal spleen lymphocytes from apoptosis both in vitro and in vivo. Additionally, it noticeably inhibited the levels of inflammatory cytokines in corpus cavernosum. Both RFEB and PFEB were safe and did not cause any clinicalsigns of toxicity in mice at the dosage of 20 times dosages of that in the Chinese Pharmacopeia. Conclusion: We demonstrated that PFEB was better than RFEB at tonifying the kidney-Yang by comparing their effects on improving the NEI network, which includes the HPA axis, immune system and corpus cavernosum. This study revealed that PFEB could significantly improve the sexual function of KDS mice by regulating the HPA axis and activating the immune system through the NEI network. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the effect of horny goat weed on the level of fertility in male rats infected with cadmium chloride. The rats were divided into two groups, the first group: Group 1 (6 rats) fed on a basal diet as a negative control group (-ve) and the other main groups (30 rats) were injected with two doses of cadmium chloride (CdCl2, 0.1%) administered intraperitoneally at 0.1 ml per 100g body weight to cause sterility and classified into five subgroups. Subgroup 1(n:6): fed on the basal diet as a positive control group (+ve). Subgroup 2 feds on basal diet and given standard drug (Sildenafil Citrate) (SC) (5 mg/kg b w) via a stomach tube daily for 28 days. Subgroup 3,4 and 5 fed on the Horny Goat Weed (HGW) by 10, 15and 20 % (w/w) of the basal diet weight, respectively. Blood samples were taken after the experiment to assess lipid profiles, liver functions, kidney functions, and serum levels of testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). The testicles were removed for histopathological examination, measuring the testicular tissue hormones and antioxidant enzymes superoxide dismutase, glutathione peroxidase, catalase and malondialdehyde. Results indicated that the HGW treatments improved liver, renal function, lipid profiles, antioxidant enzyme activity and sex hormone levels in both serum and testicular tissue. In conclusion; The moderate use of horny goat weed may be beneficial for improving male sexual performance and is considered as one of the natural sexual stimulants. [ABSTRACT FROM AUTHOR]

The basal eudicot Epimedium (Barrenwort) exhibits innovative floral morphology in the form of petal spurs filled with nectar and petaloid sepals. The B-class MADS-box genes APETALAS3 (AP3) and PISTILLA (PI) determine sepal and petal identity while the C-class gene AGAMOUS (AG) determines carpel and stamen identity in Arabidopsis. Complex histories of gene duplication resulted in subsequent subfunctionalization or neofunctionalization of paralogs. Here, a total of four B- and two C-class genes were successfully isolated from E. sagittatum. Phylogenetic analysis showed that EsAP3-1, EsAP3-2, and EsAP3-3 are part of the AP3 clade; EsPI is part of the PI group; and EsAG and EsAG11 clustered into the AG and AG11 groups, respectively. Quantitative real-time PCR was utilized to detect the expression patterns of these genes, and all B-class genes except for EsAP3-3 were found to be universally expressed. The transcribed EsAG and EsAG11 genes were confined to reproductive organs. In addition, yeast three and two hybrid assays were used to explore the status of protein complexes. EsAP3-1 was found to have broadly interactive partners, and EsPI can form a heterodimer with EsAP3-1 and EsAP3-2. Transgenic EsAG overexpression in wild-type Arabidopsis confirmed the conserved function determining carpel development.

Abstract Background Growth-promoting antibiotics have been banned by law in the livestock and poultry breeding industry in many countries. Various alternatives to antibiotics have been investigated for using in livestock. Epimedium (EM) is an herb rich in flavonoids that has many beneficial effects on animals. Therefore, this study was planned to explore the potential of EM as a new alternative antibiotic product in animal feed. Methods A total of 720 1-day-old male broilers (Arbor Acres Plus) were randomly divided into six groups and fed basal diet (normal control; NC), basal diet supplemented with antibiotic (75 mg/kg chlortetracycline; CTC), and basal diet supplemented with 100, 200, 400 or 800 mg/kg EM extract for 6 weeks (EM100, EM200, EM400 and EM800 groups). The growth performance at weeks 3 and 6 was measured. Serum, intestinal tissue and feces were collected to assay for antioxidant indexes, intestinal permeability, lactic acid and short-chain fatty acids (SCFAs) profiles, microbial composition, and expression of intestinal barrier genes. Results The average daily feed intake in CTC group at 1–21 d was significantly higher than that in the NC group, and had no statistical difference with EM groups. Compared with NC group, average daily gain in CTC and EM200 groups increased significantly at 1–21 and 1–42 d. Compared with NC group, EM200 and EM400 groups had significantly decreased levels of lipopolysaccharide and D-lactic acid in serum throughout the study. The concentrations of lactic acid, acetic acid, propionic acid, butyric acid and SCFAs in feces of birds fed 200 mg/kg EM diet were significantly higher than those fed chlortetracycline. The dietary supplementation of chlortetracycline and 200 mg/kg EM significantly increased ileal expression of SOD1, Claudin-1 and ZO-1 genes. Dietary supplemented with 200 mg/kg EM increased the relative abundances of g_NK4A214_group and Lactobacillus in the jejunal, while the relative abundances of Microbacterium, Kitasatospora, Bacteroides in the jejunal and Gallibacterium in the ileum decreased. Conclusion Supplementation with 200 mg/kg EM extract improved the composition of intestinal microbiota by regulating the core bacterial genus Lactobacillus, and increased the concentration of beneficial metabolites lactic acid and SCFAs in the flora, thereby improving the antioxidant capacity and intestinal permeability, enhancing the function of tight junction proteins. These beneficial effects improved the growth performance of broilers. Graphical Abstract

Industrial application of icariin and baohuoside I has been hindered by the short supply to a great extent. In this work, a novel GH78 α-l-rhamnosidase AmRha catalyzed the bioconversion of low-value epimedin C in crude Epimedium Folium flavonoids (EFs) to icariin and baohuoside I was developed. Firstly, the high-level expression of AmRha in Komagataella phaffii GS115 attained an enzyme activity of 571.04 U/mL. The purified recombinant AmRha could hydrolyze α-1,2-rhamnoside bond between two rhamnoses (α-Rha(2 → 1)α-Rha) in epimedin C to produce icariin with a molar conversion rate of 92.3%, in vitro. Furtherly, the biotransformation of epimedin C to icariin by the recombinant Komagataella phaffii GS115 cells was also investigated, which elevated the EFs concentration by fivefold. In addition, biotransformation of epimedins A-C and icariin in the raw EFs to baohuoside I was fulfilled by a collaboration of AmRha and β-glucosidase/β-xylosidase Dth3. The results obtained here provide a new insight into the preparation of high-value products icariin and baohuoside I from cheap raw EFs. [ABSTRACT FROM AUTHOR]

Herba Epimedii (Epimedium) leaves are rich in prenylated flavonol glycosides (PFGs) with high medicinal value. However, the dynamics and regulatory network of PFG biosynthesis remain largely unclear. Here, we combined metabolite profiling (targeted to PFGs) and a high-temporal-resolution transcriptome to elucidate PFGs' regulatory network in Epimedium pubescens and identified key candidate structural genes and transcription factors (TFs) involved in PFG accumulation. Chemical profile analysis revealed that PFG content was quite different between buds and leaves and displayed a continuous decline with leaf development. The structural genes are the determinant reasons, and they are strictly regulated by TFs under temporal cues. We further constructed seven time-ordered gene co-expression networks (TO-GCNs) of PFG biosynthesis genes (including EpPAL2, EpC4H, EpCHS2, EpCHI2, EpF3H, EpFLS3, and EpPT8), and three flavonol biosynthesis routines were then predicted. The TFs involved in TO-GCNs were further confirmed by WGCNA analysis. Fourteen hub genes, comprising 5 MYBs, 1 bHLH, 1 WD40, 2 bZIPs, 1 BES1, 1 C2H2, 1 Trihelix, 1 HD-ZIP, and 1 GATA were identified as candidate key TFs. The results were further validated by TF binding site (TFBS) analysis and qRT-PCR. Overall, these findings provide valuable information for understanding the molecular regulatory mechanism of PFGs biosynthesis, enriching the gene resources, which will guide further research on PFG accumulation in Epimedium. [ABSTRACT FROM AUTHOR]