INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
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2020
·Vol. 45
·期 3
·816-824
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IF 3.098
Wei,Wang,Hu,Xie,Ling,Gao,Cao
Icaritin, a metabolite of icariin, is a potent promoter of bone marrowderived mesenchymal stem cells (BMSCs) osteogenesis, but the underlying mechanisms remain unclear. To examine the effects of icaritin on osteogenic differentiation, BMSCs were exposed to osteogenic induction medium
with or without icaritin pretreatment in the present study. It was identified that icaritin (0.011 µM) exhibited no cytotoxicity on the proliferative abilities of the BMSCs. Icaritin at 1 µM increased alkaline phosphatase activity, mineral deposition and osteoblastspecific
gene expression. Treatment with 1 µM Icaritin upregulated osteocalcin, RUNX family transcription factor 2, tissuenonspecific alkaline phosphatase and βcatenin, and suppressed sclerostin (SOST) gene expression in different stages of osteogenic differentiation. It was also
demonstrated that SOST overexpression inhibited icaritininduced osteogenesis. The western blot analysis data suggested that ICI 182780, which causes estrogen receptor α (ERα) degradation, reversed the icaritininduced decrease in SOST expression, which was inconsistent
with the results of immunofluorescence analysis. In conclusion, icaritin was demonstrated to promote the osteogenesis of hBMSCs by downregulating SOST expression, and icaritininduced suppression of SOST was regulated in part via the Wnt/βcatenin/ERα axis.
研究领域:
药理学
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干细胞生物学
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骨骼生物学
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
·
IF 8.5
Anyi Wu,Junping Zhou,Yinan Xue,Yun Liu,Jidong Shen,Xin Gao,Zhiqiang Liu,Yuguo Zheng
Icaritin (ICT) shows various pharmacological activities and is used as an anti-hepatocellular carcinoma drug. While most of the studies focused on constructing yeast chassis cells for ICT production to replace the ICT extraction of Epimedium species, an efficient multi-enzyme system was first constructed here in the prokaryote Escherichia coli , for the successful biotransformation from naringenin (NAR) and prenol to ICT. The plant-derived flavonoid 3-hydroxylase (F3H) and flavonol synthase (FLS) were screened, and then fused together with protein linkers to efficiently catalyze the conversion of NAR to kaempferol (KAE). The isopentenol utilization (IU) pathway was subsequently introduced to increase dimethylallyl diphosphate (DMAPP) supply, along with catalytic activity improvement of prenyltransferase (PT) using N -terminal truncations and active site pocket engineering. Furthermore, by screening O -methytransferases (OMT) from different sources, EpOMT 4 from Epimedium pseudowushanense was selected for the ICT production. With the combination of these strategies, 80.8 ± 3.6 mg/L ICT could be produced from NAR and prenol in the recombinant E. coli , from the original 0 % degree of conversion. The systematic engineering of multi-enzyme system for ICT biosynthesis has laid the foundation for the large-scale ICT production using the industrially important E. coli chassis cell.
研究领域:
合成生物学
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代谢工程
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微生物生物技术
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酶工程
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天然产物生物合成
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2026
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IF 6.7
Guohua Ma,Yuan Gao,Kaiyue Zhang,Hongyu Zhao,Wenyan Gao,Yufang He,Yuwei Zhao,Minlun Nan
Icaritin was prepared from Epimedium leaves via a green enzymatic-acid route. • Five N-Boc-amino acid esters of icaritin (M1-M5) were synthesized in 75-90% yield. • M1 inhibited α-glucosidase ( IC 50 = 5.5 nM), outperforming acarbose and ICT. • M1 improved glucose uptake and reduced oxidative stress in IR-HepG2 cells. • Molecular docking and MD simulations suggest a structural basis for M1's potency. Type 2 diabetes increasingly calls for multi-target therapies that act along the intestinal-hepatic axis rather than at a single node, yet few chemical strategies have been designed to pursue both nodes from a single natural scaffold. Icaritin (ICT), the principal bioactive metabolite of the Epimedium flavonoid icariin, has long been used in traditional Chinese medicine to relieve metabolic wasting-thirst disturbances resembling diabetes and shows promising hypoglycemic activity. However, its free phenolic hydroxyl groups confer extensive hydrogen bonding with water, a structural feature expected to limit aqueous solubility and membrane permeability. Here, ICT was prepared from Epimedium leaves via a green enzyme-assisted hydrolysis route and converted, in synthetically useful yields (75-90%), into five N-Boc-amino acid ester derivatives (M1-M5) designed to mask its reactive phenolic hydroxyls while adding tunable lipophilic bulk. The N-Boc- l -proline ester M1 was the most potent α-glucosidase inhibitor ( IC 50 = 5.5 ± 0.5 nM), 1.5-fold and 2.0-fold more active than its parent ICT (8.3 ± 0.5 nM) and acarbose (11.0 ± 0.6 nM), and remained intact in simulated gastric and intestinal fluids. Docking and 100 ns molecular dynamics simulations provided preliminary structural insights into the possible interaction of M1 with α-glucosidase, with the rigid N-Boc-pyrrolidine group positioned in a hydrophobic cleft near the active site. In palmitate-induced insulin-resistant HepG2 cells, M1 (20 μM) increased glucose consumption by 58.1% over the model group, lowered intracellular ROS to approximately 2.6-fold of control, and reduced lipid accumulation to a level comparable to metformin. These effects were accompanied by downregulation of glucose-6-phosphatase and upregulation of catalase, without significantly altering basal glucose consumption in normal HepG2 cells. Together, these findings establish a scalable route to ICT and demonstrate that esterification of its phenolic hydroxyl groups can modify α-glucosidase inhibition and cellular metabolic phenotypes, identifying M1 as a lead compound meriting in vivo validation. Download: Download high-res image (387KB) Download: Download full-size image
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DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY
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2026
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IF 2.6
Xiaoxian Yao,Weidong Ye,Pingfu Huang,Xiangming Fang
Purpose To overcome the poor aqueous solubility limitations of Icaritin (ICT) and Piperine (PIP), which restrict their therapeutic potential, by developing a co-amorphous drug delivery system.Significance The co-amorphous strategy presents a promising solution to enhance solubility, dissolution rate, and oral bioavailability of poorly water-soluble drug combinations, thereby improving their pharmaceutical applicability.Methods The optimal 1:1 molar ratio of ICT-PIP was determined through in vitro anti-inflammatory evaluation and combination modeling. Molecular dynamics simulations were employed to investigate intermolecular interactions, while Powder X-Ray Diffraction (PXRD), Fourier Transform Infrared Spectroscopy (FT-IR), and Differential Scanning Calorimetry (DSC) analyses were used to confirm co-amorphous formation and characterize solid-state properties.Results The ICT-PIP co-amorphous system demonstrated significantly improved solubility (3.5-fold for ICT, 3.7-fold for PIP) and intrinsic dissolution rate (2.0-fold for ICT and 1.8-fold for PIP) compared to crystalline forms. PXRD confirmed complete amorphization with no detectable crystalline peaks, FT-IR revealed intermolecular hydrogen bonding interactions between ICT and PIP, and DSC showed a single glass transition temperature (Tg) at 164.6 °C, confirming single-phase amorphous system formation. Pharmacokinetic studies revealed 1.6-fold and 1.4-fold enhancements in oral bioavailability for ICT and PIP, respectively. The system maintained excellent physical stability for six months under storage conditions.Conclusion This study successfully developed a stable ICT-PIP co-amorphous system with superior solubility and bioavailability characteristics, demonstrating the effectiveness of co-amorphization as a viable strategy for optimizing the delivery of poorly soluble drug combinations.
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JOURNAL OF CHROMATOGRAPHY A
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2026
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IF 4
Xinhua Li,Boyu Hao,Xiao Wang,Ruya Wang,Wenchong Tang,Suxin Pan,Wenrui Yin,Mengyuan Zhang,Mingyuan Gao,Weidong Zhang
A magnetic icaritin-imprinted polymer was developed for selective aglycone depletion. • Time-resolved LC–MS/MS profiling revealed formation of icaritin-type aglycones during fermentation. • The imprinted polymer enabled controlled removal of icaritin from fermented matrices. • Selective aglycone depletion attenuated cartilage-promoting activity in zebrafish. • An analytical depletion strategy was established for metabolite–activity causality analysis. Establishing causal relationships between individual metabolites and biological activity in complex natural product systems remains a significant analytical challenge, as conventional chromatographic profiling is largely limited to correlation-based interpretation. In this study, a chromatography-guided analytical intervention strategy was developed based on a magnetic molecularly imprinted polymer (MMIP) to enable selective and quantitative manipulation of target metabolites in fermented Epimedium flavonoids. Time-resolved UPLC–MS/MS profiling revealed rapid microbial deglycosylation of prenylated flavonoid glycosides, accompanied by the accumulation of icaritin-type aglycones, particularly icaritin and desmethylicaritin. An icaritin-imprinted MMIP was synthesized and systematically characterized, exhibiting high binding capacity (58.14 mg g⁻¹), favorable adsorption kinetics, and selective recognition toward target aglycones. Under optimized conditions, the MMIP enabled controlled depletion of icaritin from fermented matrices, and residual levels were accurately quantified by a validated HPLC–UV method, achieving a removal efficiency of 84.5%. Selective removal of aglycones resulted in a pronounced attenuation of cartilage-promoting effects in zebrafish models, and the magnitude of functional loss was quantitatively correlated with the degree of depletion, providing direct evidence of metabolite–activity causality. Compared with conventional fractionation approaches, the proposed strategy enables selective chromatographic modulation of target analytes with minimal disturbance to the surrounding chemical matrix, extending chromatographic analysis from passive profiling to active molecular intervention and providing a generalizable framework for causality-oriented metabolite identification in complex systems.
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Cancers
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2026
·Vol. 18
·期 5
·804
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IF 4.8
Jimeng Hu,Yingchun Liang,Xiaobo Wu,Jianhua Huang,Haowen Jiang
Simple SummaryOur study investigated the mechanisms by which Icaritin (ICT) suppresses prostate cancer (PCa) progression via modulation of the gut microbiome. Using C57BL/6 and TRAMP mouse models, we found that a high-fat diet (HFD) significantly reduced in-testinal Akkermansiaceae abundance and vitamin K2 levels relative to control di-et-fed mice. ICT supplementation in HFD-fed TRAMP mice restored Akkermansiaceae pop-ulations and elevated vitamin K2 levels, concurrently decreasing serum leptin and in-creasing adiponectin concentrations. Direct gavage with Akkermansiaceae similarly elevated vitamin K2 levels, improved adipokine profiles, and extended survival. These findings demonstrate that ICT exerts anti-tumor effects by modulating gut Akker-man-siaceae, thereby enhancing vitamin K2 production and regulating adipokine se-cretion, which supports its clinical potential for PCa treatment.Background:High-fat diet (HFD) induced inflammation and tumorigenesis by altering gut microenvironment and gut microbiome profiles. Vitamin K2 along withAkkermansiaceae, an intestinal symbiote, is involved in anti-tumors including prostate cancer (PCa). Although there have been clinical studies of Icaritin (ICT) for anti-tumor, its detailed mechanism for anti-PCa remains unclear. Here, we explored the effect of ICT on PCa progression that involved altering the mouse gut microbiome.Methods:We used 20 C57BL/6 mice and 85 transgenic adenocarcinomas of mouse prostate (TRAMP) mice as animal models. Then, 16SrRNA pyrophosphate gene sequencing was used to analyze the intestinal fecal microbiome of mice in each group. At the same time, vitamin K2 in fecal samples was determined by High Performance Liquid Chromatography (HPLC), and the content of adipokines leptin and adiponectin in serum was determined by Elisa.Results:It was observed that the relative abundance ofAkkermansiaceae(9.14 ± 2.75% (C57BL/6J-N) vs. 5.66 ± 1.35% (C57BL/6J-HFD); 1.21 ± 0.61% (TRAMP-N) vs. 0.67 ± 0.45% (TRAMP-HFD) (p< 0.05) and vitamin K2 (C57BL/6J-HFD was 0.41-fold to C57BL/6J-N, TRAMP-HFD was 0.71-fold to TRAMP-N) in the intestinal fecal of HFD C57BL/6 and TRAMP were significantly lower than those of control mice. Both the ratio ofAkkermansiaceaeand vitamin K2 in the gut fecal were significantly increased in HFD-fed TRAMP mice supplemented with ICT compared with HFD-fed TRAMP group (p< 0.01). When HFD TRAMP mice were fed withAkkermansiaceaeby gavage, the content of vitamin K2 in the intestinal fecal of the mice was increased, the adipokines leptin in the serum were decreased, but the adiponectin was significantly increased, and the overall survival time of the TRAMP mice was significantly prolonged. Our study shows that ICT rescued the reduction inAkkermansiaceaein the gut microbiota of HFD TRAMP mice. ICT suppresses PCa by modulatingAkkermansiaceaein the gut, increasing vitamin K2, and regulating adipokines leptin and adiponectin secretion.Conclusions:Our study suggested that ICT might regulate abundance ofAkkermansiaceaeto increase vitamin K2 to suppress PCa. This provides theoretical basis and data support for the clinical application of ICT in the treatment of PCa.
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Nano Research
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2024
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IF 9.5
Wang Peng,Wang Qianjin,Wu Dengxian,Zhang Yunyang,Kang Shixiong,Wang Xucai,Gu Jiayu,Wu Hao,Xu Zhihong,Jiang Qing
Bone tissue engineering provides a promising strategy for the treatment of bone defects. Nonetheless, the clinical utilization of biomaterial-based scaffolds is constrained by their inadequate mechanical strength and absence of osteo-inductive properties. Here, we proposed to endow nano-scaffold (NS) constructed by coaxial electrospinning technique with enhanced osteogenic bioactivities and mechanical properties by incorporating biocompatible magnetic iron oxide nanoparticles (IONPs) and icaritin (ICA). Four types of nano-scaffolds (NS, ICA@NS, NS-IONPs and ICA@NS-IONPs) were prepared. The incorporation of ICA and IONPs minimally impact their surface morphological and chemical properties. IONPs enhanced the mechanical properties of NS scaffolds, including hardness, tensile strength, and elastic modulus. In vitro assessments demonstrated that ICA@NS-IONPs exhibited enhanced osteogenic bioactivities towards mouse calvarial pre-osteoblast cell line MC3T3-E1 as evidenced by detecting the alkaline phosphatase (ALP) activity level, expressions of osteogenesis-related genes and proteins as well as mineralized nodule formation. Mechanistic investigations revealed that MEK/ERK (MAP kinase-ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK)) signaling pathway could offer a plausible explanation for the osteogenic differentiation of MC3T3-E1 cells induced by ICA@NS-IONPs. Furthermore, the implantation of nano-scaffolds in rat skull defects exhibited a substantial improvement in in vivo bone regeneration. Therefore, IONPs and ICA incorporated coaxial electrospinning nano-scaffolds present a novel strategy for the optimization of scaffolds for bone tissue engineering.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
·
IF 7.7
Jingjing Zhang,Jing Huang,Yufan Yang,Daxin Zhao,Cong Wang,Peng Zhong,Jianhua Jia,Weifan Dang,Qiwei Lu,Chengyu Zhang,Xiaohui Yan
Icaritin (ICT), a compound with diverse biological activities derived from Epimedium folium, is typically present in low concentrations in EFs. However, the abundant glycosyl-modified ICT compounds facilitate its transformation into ICT. Current biocatalytic production faces challenges, including low conversion rates and limited enzyme activity. This study developed a one-pot enzymatic cascade strategy for directly biotransform crude extracts of Epimedium folium (EEF) to produce ICT. The feasibility of catalyzing different ICT-related compounds in EEF was validated through molecular docking and substrate reactions. The selected glycosidase exhibited simultaneous activities as a glucosidase, xylosidase, and α-1,6-rhamnosidase, with the rhamnosidase showing outer-rhamnosidic activity and weak glucosidase activity. By using EFs as the substrate and employing whole-cells ( Escherichia coli ) containing LacS and BtRha proteins for synergistic catalysis, icariin can be efficiently synthesized within 6 h, achieving a conversion rate of 100 %. The enzymatic cascade for ICT production from crude extracts was elucidated by analyzing catalytic intermediates via HPLC. Compared to strategies using single or traditional multi-enzyme applications, this method shows advantages of ease to operation, high efficiency, and large production yield performance. This method has the potential to become an eco-friendly catalytic strategy for the large-scale production of icaritin.
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FOOD RESEARCH INTERNATIONAL
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2025
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IF 8
Chang-Yu Yan,Xiao-Yuan Gu,Shuo-Yan Tan,Ao-Yu Mei,Jiang-Hao Mao,Yi Dai,Jie Niu,Wei-Xi Li,Hiroshi Kurihara,Yi-Fang Li,Rong-Rong He
This study provides a comprehensive evaluation of the anti-osteoporotic effects of flavonoids derived from Epimedium , including icaritin and its six glycosides—icariside I, icariside II, icariin, epimedin A, epimedin B, and epimedin C—using a zebrafish model of iron overload-induced osteoporosis. Our results demonstrate a significant increase in lipid peroxidation in zebrafish subjected to ferric ammonium citrate (FAC)-induced osteoporosis, along with impaired expression and activity of glutathione peroxidase 4 (GPX4). Treatment with ferrostatin-1, a lipid peroxide scavenger, partially alleviated the osteoporotic effects induced by FAC, implying that lipid peroxidation may play a key role in iron overload-related osteoporosis. We observed varying degrees of anti-osteoporotic activity and enhancement of osteogenic differentiation markers, such as bmp2b , runx2b , col1a1a , and alp , among icaritin and its glycosides. Notably, icaritin exhibited the most potent inhibitory effects on osteoporosis, while epimedin A and epimedin B showed enhanced efficacy compared to other glycosides, correlating closely with their ability to suppress lipid peroxidation. Additionally, through CETSA, molecular docking, and dynamic simulation studies, we identified an interaction between icaritin and GPX4, which may help stabilizing GPX4 against FAC-induced lipid peroxidation. These findings suggest that the anti-osteoporotic effects of icaritin and its glycosides are linked to their ability to suppress lipid peroxidation, offering potential therapeutic insights for managing iron overload-induced osteoporosis.
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Antioxidants
·
2024
·Vol. 13
·期 10
·1183
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IF 6
Hao Wu,Zhen-Hua Zhang,Ping Zhou,Xin Sui,Xi Liu,Yi Sun,Xin Zhao,Xiao-Ping Pu
Degeneration and death of dopaminergic neurons in the substantia nigra of the midbrain are the main pathological changes in Parkinson’s disease (PD); however, the mechanism underlying the selective vulnerability of specific neuronal populations in PD remains unclear. Here, we used single-cell RNA sequencing to identify seven cell clusters, including oligodendrocytes, neurons, astrocytes, oligodendrocyte progenitor cells, microglia, synapse-rich cells (SRCs), and endothelial cells, in the substantia nigra of a rotenone-induced rat model of PD based on marker genes and functional definitions. We found that SRCs were a previously unidentified cell subtype, and the tight interactions between SRCs and other cell populations can be improved by icaritin, which is a flavonoid extracted fromEpimedium sagittatumMaxim. and exerts anti-neuroinflammatory, antioxidant, and immune-improving effects in PD. We also demonstrated that icaritin bound with transcription factors of SRCs, and icaritin application modulated synaptic characterization of SRCs, neuroinflammation, oxidative stress, and survival of dopaminergic neurons, and improved abnormal energy metabolism, amino acid metabolism, and phospholipase D metabolism of astrocytes in the substantia nigra of rats with PD. Moreover, icaritin supplementation also promotes the recovery of the physiological homeostasis of the other cell clusters to delay the pathogenesis of PD. These data uncovered previously unknown cellular diversity in a rat model of Parkinson’s disease and provide insights into the promising therapeutic potential of icaritin in PD.
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BRITISH JOURNAL OF CANCER
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2026
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IF 7.8
Zhao Kun,Zhang Jian,Wang Ran,Wang Bin,Ye Dongfan,Huang XiaoOu,Qiu Lingxiao,Duan Yi,Xu Zhi
Background EGFR-tyrosine kinase inhibitors (EGFR-TKIs) prolong the survival of patients with non-small cell lung cancer (NSCLC); however, drug resistance limits their long-term efficacy. The role of STAT3 signaling in EGFR-TKI resistance is not completely understood. Methods Using immunohistochemistry, we assessed changes in STAT3 phosphorylation levels in NSCLC before and after EGFR-TKIs treatment. Through gene editing and transcriptome sequencing experiments, we investigated the mechanism by which STAT3 signaling mediates drug resistance. We conducted cell proliferation and nude mice tumorigenesis experiments to verify whether STAT3 inhibitors enhanced the anti-tumor effect of EGFR-TKIs on NSCLC. Results We found that inhibition of the MAPK pathway by EGFR-TKIs triggers the rapid activation of STAT3 in NSCLC. RNA-seq analysis and cellular experiments confirmed that STAT3 regulates the expression of stemness markers, which contribute to drug resistance. Cancer stemness maintenance depends on telomerase. We found that STAT3 also mediates NSCLC resistance by regulating telomerase expression. Finally, we demonstrated in both cellular and animal models that icaritin, an anti-hepatocellular carcinoma agent, significantly potentiates the anti-tumor efficacy of EGFR-TKIs against NSCLC by inhibiting STAT3 activation. Conclusions The combination of EGFR-TKIs and STAT3 inhibitors has the potential to be a better therapeutic strategy for EGFR-mutant NSCLC than EGFR-TKI monotherapy. The alternative text for this image may have been generated using AI.
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JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
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2024
·Vol. 43
·期 1
·1-20
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IF 11.4
Xu Wenjing,Li Yingqiu,Liu Lumei,Xie Jing,Hu Zongren,Kuang Shida,Fu Xinying,Li Bonan,Sun Tiansong,Zhu Congxu,He Qinghu,Sheng Wen
Background Prostate cancer (PCa) incidence and mortality rates are rising. Our previous research has shown that the combination of icariin (ICA) and curcumol (CUR) induced autophagy and ferroptosis in PCa cells, and altered lipid metabolism. We aimed to further explore the effects of the combination of ICA and CUR on gut microbiota, metabolism, and immunity in PCa. Methods A mouse subcutaneous RM-1 cell tumor model was established. 16 S rRNA sequencing was performed to detect changes in fecal gut microbiota. SCFAs in mouse feces, and the effect of ICA-CUR on T-cell immunity, IGFBP2, and DNMT1 were examined. Fecal microbiota transplantation (FMT) was conducted to explore the mechanism of ICA-CUR. Si-IGFBP2 and si/oe-DNMT1 were transfected into RM-1 and DU145 cells, and the cells were treated with ICA-CUR to investigate the mechanism of ICA-CUR on PCa development. Results After treatment with ICA-CUR, there was a decrease in tumor volume and weight, accompanied by changes in gut microbiota. ICA-CUR affected SCFAs and DNMT1/IGFBP2/EGFR/STAT3/PD-L1 pathway. ICA-CUR increased the positive rates of CD3 + CD8 + IFN-γ, CD3 + CD8 + Ki67 cells, and the levels of IFN-γ and IFN-α in the serum. After FMT (with donors from the ICA-CUR group), tumor volume and weight were decreased. SCFAs promote tumor development and the expression of IGFBP2. In vitro, DNMT1/IGFBP2 promotes cell migration and proliferation. ICA-CUR inhibits the expression of DNMT1/IGFBP2. Conclusions ICA-CUR mediates the interaction between gut microbiota and the DNMT1/IGFBP2 axis to inhibit the progression of PCa by regulating immune response and metabolism, suggesting a potential therapeutic strategy for PCa.
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