MOLECULES
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2025
·Vol. 30
·期 8
·1667
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IF 4.6
Zenan Chen,Wei Li,Yan Zhao,Dingrui Liu,Jiahong Han,Enbo Cai
Tumorigenesis and progression are closely associated with apoptosis and primarily regulated by mitochondria, which are considered major targets for cancer therapy. In this study, twelve novel icaritin (ICT) derivatives were designed and synthesized, four of which were specifically targeted to mitochondria. Biological studies demonstrated that all compounds containing triphenylphosphine (TPP+) exhibited a substantial increase in antitumor activity compared to ICT and control compounds while also exhibiting notable selectivity for tumor cells over normal cells. Among these derivatives, Mito-ICT-4 exhibited the strongest antiproliferative effect, with an IC50value of 0.73 ± 0.06 μM for BEL-7402 cells, which is 29 times lower than that of ICT, and an IC50value of 67.11 ± 2.09 μM for HEK293 cells, indicating approximately 33-fold selectivity for tumor cells. High-performance liquid chromatography (HPLC) analysis revealed that Mito-ICT-4 significantly accumulated in the mitochondria of BEL-7402 cells, with the level of accumulation approximately 2.5 times greater than that of ICT. Further investigations demonstrated that upon entering the mitochondria of tumor cells, Mito-ICT-4 downregulated SIRT3 protein expression, disrupted intracellular redox homeostasis, and led to a substantial increase in mitochondrial ROS levels, abnormal CypD-dependent MPTP opening, mitochondrial membrane potential depolarization, and ROS release into the cytoplasm, ultimately triggering ROS-mediated apoptosis in BEL-7402 cells. Transcriptomic analysis identified differentially expressed genes and enriched pathways, highlighting the ROS-mediated p38-MAPK signaling pathway as a key mediator of Mito-ICT-4-induced mitochondria-dependent apoptosis. The effects of Mito-ICT-4 on the expression of key genes (SIRT3, CypD, P-MKK6, P-P38, and DDIT3) were further validated by qRT-PCR and Western blot analysis, with results aligning with transcriptomic data. The novel ICT derivatives synthesized in this study, with mitochondria-targeting functionality, provide a basis for the development of targeted antitumor drugs.
研究领域:
肿瘤学
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药理学
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分子生物学
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PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2015
·
IF 3.447
Chen Wang,Ping Wu,Jing-Fang Shi,Zi-Hua Jiang,Xiao-Yi Wei
A series of icaritin derivatives bearing carboxylic acid or carboxylic ester groups are synthesized, and their in vitro cytotoxic activity against three cancer cell lines, MCF-7, MDA-MB-435s, and A549, are evaluated by MTT assay . Several derivatives including 2h , 2j , 5b and 5d show higher cytotoxic activity than the parent compound icaritin against these cancer cell lines. Compounds 5b and 5d are even more cytotoxic to MCF-7 cells than the clinic drug tamoxifen . Moreover, compound 5b is found to be non-toxic to normal cells (Vero) and both 5b and 5d exhibit good selectivity towards estrogen receptor positive MCF-7 breast cancer cells over estrogen receptor negative MDA-MB-435s breast cancer cells. The structure activity relationship analysis has revealed that mono-substitution at either C-3 or C-7 hydroxyl group of icaritin could improve the cytotoxicity of icaritin, and the C-3 hydroxyl group may be a preferable site for chemical modification. In addition, the length, the flexibility and the additional branching substituent group of the substitution chain(s) at both C-3 and C-7 hydroxyl groups can all affect the anti-cancer activity of these derivatives.
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PubMed
高影响因子
Microbial Cell Factories
·
2023
·Vol. 22
·期 1
·1-11
·
IF 6.4
Lin Yu,Chen Wen-wen,Ding Bo,Guo Man,Liang Meng,Pang Hao,Wei Yu-tuo,Huang Ri-bo,Du Li-qin
Background Icaritin is an aglycone of flavonoid glycosides from Herba Epimedii. It has good performance in the treatment of hepatocellular carcinoma in clinical trials. However, the natural icaritin content of Herba Epimedii is very low. At present, the icaritin is mainly prepared from flavonoid glycosides by α-L-rhamnosidases and β-glucosidases in two-step catalysis process. However, one-pot icaritin production required reported enzymes to be immobilized or bifunctional enzymes to hydrolyze substrate with long reaction time, which caused complicated operations and high costs. To improve the production efficiency and reduce costs, we explored α-L-rhamnosidase SPRHA2 and β-glucosidase PBGL to directly hydrolyze icariin to icaritin in one-pot, and developed the whole-cell catalytic method for efficient icaritin production.Results The SPRHA2 and PBGL were expressed in Escherichia coli, respectively. One-pot production of icaritin was achieved by co-catalysis of SPRHA2 and PBGL. Moreover, whole-cell catalysis was developed for icariin hydrolysis. The mixture of SPRHA2 cells and PBGL cells transformed 200 g/L icariin into 103.69 g/L icaritin (yield 95.23%) in 4 h in whole-cell catalysis under the optimized reaction conditions. In order to further increase the production efficiency and simplify operations, we also constructed recombinant E. coli strains that co-expressed SPRHA2 and PBGL. Crude icariin extracts were also efficiently hydrolyzed by the whole-cell catalytic system.Conclusion sCompared to previous reports on icaritin production, in this study, whole-cell catalysis showed higher production efficiency of icaritin. This study provides promising approach for industrial production of icaritin in the future.
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PubMed
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ACS Applied Nano Materials
·
2022
·
IF 6.14
Kaijia Zhang,Jian Dong,Jun Lu,Lan Li,Huan Liang,Jing Jin,Peng Wang,Xiaolian Sun,Qing Jiang
Bone fracture is a huge medical and sociological problem. Among various therapeutic drugs, icaritin (ICA), as a novel natural osteoinductive agent, has attracted considerable attention due to its remarkable osteogenic effect, but it still has some drawbacks such as poor bone targeting and a rapid plasma clearance rate. Recently, iron oxide nanoparticles (IONPs) show increasingly potential as drug delivery vehicles to overcome these limitations. In this study, porous hollow iron oxide nanoparticles (PHNPs) were synthesized via thermal decomposition and controllable oxidation methods and ICA was incorporated during the hydrophilic phase transfer process. The preosteoblastic MC3T3-E1 cell line was used to evaluate their osteogenic effect, and the results demonstrated that ICA-incorporated PHNPs displayed superior biocompatibility and pronounced alkaline phosphatase activity and expression of osteogenic-related genes and proteins in a synergistic manner. Mechanistic investigations demonstrated that the MEK/ERK/p90RSK signaling pathway might provide a potential explanation for ICA-incorporated PHNP-mediated osteogenic differentiation. Furthermore, hyaluronic acid–cholesterol (HA–CHOL) was used to establish nanoclusters (ICA-PHNP-NCs) for in vivo bone regeneration assessment using a murine femur fracture as a model. The results showed that ICA-PHNP-NCs efficiently accumulated at the fracture site in the presence of a static magnetic field and accelerated fracture repair rapidly and effectively. For the first time, the dual application of osteogenic agents transport and ICA delivery using the ICA-PHNP-NC formulation was achieved against bone fracture, providing a new treatment strategy for diseases related to fractures.
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MOLECULAR BIOLOGY REPORTS
·
2026
·Vol. 53
·期 1
·1444
·
IF 3.2
He Yalun,Ding Jie,Li Yangshuo,Sun Ji,Wei Cuiping,Sun Na,Jiang Runnan,Zhao Ziming,Liang Xiaolan,Chen Yiming,Cheng Wen,Zhang Litai,Song Di,Sun Shuai,Yu Chaoqin
Background Endometriosis (EMS) is an oestrogen-dependent chronic inflammatory disease that primarily manifests as chronic pelvic pain and infertility. EMS-associated infertility is closely linked to diminished ovarian function and oocyte quality, with the aberrant function of granulosa cells (GCs). Cellular senescence has a nonnegligible effect on female fertility. GCs in EMS patients may undergo senescence, subsequently compromising their nutritional support to oocytes and impairing ovarian function, ultimately contributing to infertility. Icaritin (Ica) possesses various biological activities including anti-tumour, anti-inflammatory, anti-oxidation and anti-aging. Methods Follicular fluid (FF) was collected from normal control females and EMS patients. GCs were extracted from FF for RNA sequencing and bioinformatic analysis. NADH: ubiquinone oxidoreductase core subunit S8 (NDUFS8)-knockdown KGN cells were established using shRNA-mediated lentiviral transduction. Pro-oxidants and oxidation scavengers were employed to modulate reactive oxygen species (ROS) levels. Network pharmacology was employed to analyse potential mechanisms of Ica in treating EMS. Ica was employed to intervene EMS-FF-treated KGN cells and EMS mice. Results Ica significantly reduced degrees of peritoneal adhesions, decreased quantities and volumes of ectopic lesions and improved reproductive capacity in EMS mice. Moreover, Ica may inhibit ovarian GC senescence and improve ovarian function in EMS mice by regulating NDUFS8/ROS/P53/P21 axis. In vitro experiments demonstrated that Ica may inhibit EMS-FF-induced KGN cell senescence by regulating NDUFS8/ROS/P53/P21 axis. Conclusions These findings identify Ica as a GC senescence-inhibiting agent with therapeutic potential in EMS-associated infertility.
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高影响因子
PROCESS BIOCHEMISTRY
·
2025
·
IF 4
Yuxuan Zhao,Ye Li,Wenting Fei,Hao Liang
In recent years, nanomaterials have emerged as prominent carriers in biomedical applications. This trend aims to address limitations inherent in traditional enzyme immobilization methods and reduce the costs associated with enzyme biocatalysts in industrial processes. In this study, we selected non-toxic magnetic nanoparticles (MNPs), distinguished by their exceptional biocompatibility, as immobilization carriers to overcome the inherent instability and non-reusability of free enzymes. The MNPs were coated with chitosan to form a protective layer, thereby significantly enhancing enzyme stability. This approach also circumvented the need for precipitants, thereby avoiding the associated damage observed in conventional cross-linking. Building upon this foundation, glucosidase and rhamnosidase were immobilized onto these modified MNPs for converting Epimedin C into Icaritin. Compared to conventional cross-linked enzyme aggregation techniques, this system exhibited superior catalytic efficiency. Furthermore, the immobilized enzyme system enables rapid magnetic separation of the reaction product. Notably, the immobilized enzymes retained approximately 70 % of their initial activity after eight reuse cycles, demonstrating significant potential for industrial-scale applications. These findings demonstrate the potential of chitosan-modified magnetic nanoparticles as efficient, reusable enzyme carriers for sustainable biocatalytic processes in pharmaceutical and industrial applications.
研究领域:
纳米技术
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酶工程
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制药生物技术
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工业生物催化
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材料科学
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DOI
高影响因子
LIFE SCIENCES
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2021
·
IF 5.037
Yue Xiong,Yan Chen,Xinping Huang,Zhen Yang,Jiaye Zhang,Xiaorui Yu,Ji Fang,Jiawang Tao,Kai You,Ziqi Cheng,Shenglin Tan,Yingying Xu,Fang Yuan,Ying Liu,Yuanqi Zhuang,Fan Yang,Yinxiong Li
Aim This study aimed to reveal the effects of icaritin (ICT) on lipotoxicity induced by palmitate (PA) in hepatic cells and steatosis in high-fat diet (HFD)-fed mice as well as exploring the potential mechanisms. Main methods Primary mouse hepatocytes and human hepatoma Huh7 cells were used to evaluate ICT effect in vitro. HFD-fed mice were used to evaluate the ICT effect in vivo. Results In vitro study indicated that ICT significantly rescued PA-induced steatosis, mainly through a combination of robust increased mitochondrial respiration, fatty acid oxidation and mildly decreased synthesis of fatty acid. An HFD-fed mouse model with 8 weeks HFD-fed showed metabolic disorders, while ICT application significantly reduced the weight, serum glucose levels, insulin resistance, hepatic steatosis level and adipose contents. In consistent with the observations in cell lines, ICT rescued the HFD-impaired functions and contents of key factors related to fatty acid β-oxidation through elevated expression of peroxisome proliferator-activated receptor α (PPARα). Meanwhile, it also reversed the decreased phosphoryl levels of AKT and glucogen synthase kinase 3 (GSK3β), leading to the improvement of insulin resistance. Significance ICT administration had a therapeutic effect on PA- or HFD-induced hepatic steatosis and metabolic disorders. It may provide a novel strategy to construct preventive and therapeutic means for hepatic steatosis.
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PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Xinyi Li,Yuyi Qian,Xin Lu,Mingzhen Xu,Simin He,Jianping Zhang,Shaoli Song
Transarterial radioembolization (TARE) is a recommended locoregional strategy for intermediate hepatocellular carcinoma (HCC), whereas, the effect is insufficient to reverse the immunosuppression tumor microenvironment, and the overall benefits for patients remain to be improved. In this study, a multifunctional microsphere (MS) 131 I-ICT/R848-MS is developed to propose an approach combined with TARE, icaritin (ICT) and immune modulator resiquimod (R848). ICT and iodine-131 ( 131 I) radiation can induce immunogenic cell death, which, in combination with R848, will boost dendritic cell (DC) maturation. Decellularized liver model and SPECT/CT imaging revealed high specificity and long retention of microspheres. Radioactive distribution of 131 I in tumor on 7 d following 131 I-MS injection was over 7 times of that in normal liver tissue (4.26 ± 1.21 % ID/g vs 0.57 ± 0.23 % ID/g). 131 I-ICT/R848-MS embolization brought significant immune activation, where the ratio of cytotoxic T lymphocytes to regulatory T cells in tumor sites upregulated from 1.75 ± 0.20 to 24.31 ± 1.79, and DC maturation in lymph nodes increased from 8.90 ± 1.51 % to 34.70 ± 3.12 %. Enhanced anti-tumor efficacy with no relapse was proved in rat orthotopic N1S1 HCC models. These results demonstrated the great potential of this multifunctional embolic agent to treat HCC through transarterial radio-immuno-chemoembolization (TARICE).
研究领域:
肿瘤学
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放射肿瘤学
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免疫疗法
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医学影像
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药理学
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DOI
PubMed
高影响因子
Antioxidants
·
2021
·Vol. 10
·期 4
·529
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IF 6.313
Hao Wu,Xi Liu,Ze-Yu Gao,Ming Lin,Xin Zhao,Yi Sun,Xiao-Ping Pu
Neuroinflammation, oxidative stress, and mitochondrial dysfunction are all important pathogenic mechanisms underlying motor dysfunction and dopaminergic neuronal damage observed in patients with Parkinson’s disease (PD). However, despite extensive efforts, targeting inflammation and oxidative stress using various approaches has not led to meaningful clinical outcomes, and mitochondrial enhancers have also failed to convincingly achieve disease-modifying effects. We tested our hypothesis that treatment approaches in PD should simultaneously reduce neuroinflammation, oxidative stress, and improve alterations in neuronal energy metabolism using the flavonoid icaritin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Using matrix-assisted laser desorption/ionization–mass spectrometry imaging (MALDI-MSI), coupled with biochemical analyses and behavioral tests, we demonstrate that icaritin improves PD by attenuating the the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome activity and stabilizing mitochondrial function, based on our extensive analyses showing the inhibition of NLRP3 inflammasome, reduction of NLRP3-mediated IL-1β secretion, and improvements in the levels of antioxidant molecules. Our data also indicated that icaritin stabilized the levels of proteins related to mitochondrial function, such as voltage-dependent anion channel (VDAC) and ATP synthase subunit beta (ATP5B), as well as those of molecules related to energy metabolism, such as ATP and ADP, ultimately improving mitochondrial dysfunction. By employing molecular docking, we also discovered that icaritin can interact with NLRP3, VDAC, ATP5B, and several blood–brain barrier (BBB)-related proteins. These data provide insights into the promising therapeutic potential of icaritin in PD.Keywords:icaritin;Parkinson’s disease;1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine;inflammation;oxidative stress;mitochondrial disfunction
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Catalysts
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2025
·Vol. 15
·期 11
·1034
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IF 4
Yuxuan Zhao,Wei Zhang,Ye Li,Wenting Fei,Hao Liang
With the booming development of natural anticancer agents, icaritin has been widely used in clinical liver cancer treatment due to the smaller number of side effects. Among them, enzymes as catalysts for producing icaritin have attracted considerable attention. Industrial production remains in its infancy due to the poor reusability of free enzymes, despite enzymes possessing favorable efficiency and green catalytic effects. The present study investigated two immobilization methods, including cross-linked enzyme aggregates (CLEAs) and magnetic cross-linked enzyme aggregates (MCLEAs). The optimal temperature and pH for the two hydrolases were determined, followed by characterization using VSM, XRD, FT-IR, and TEM techniques. The experiments have demonstrated that MCLEAs eradicate the need for ultrafiltration; MCLEAs are beneficial for enhancing fixation efficiency. Additionally, MCLEAs exhibited significantly higher catalytic activity, which raised the catalytic activity by approximately 30% compared with CLEAs. Moreover, after 10 consecutive reuse cycles, the catalytic activity of MCLEAs remained above 70%, maintaining a conversion rate of epimedin C at 61.59%. To summarize, MCLEAs offer an efficient strategy for enzyme immobilization. MCLEAs not only significantly enhanced both the enzyme’s ability to catalyze and resist but also eliminated the necessity for ultrafiltration as well as enabled rapid product separation.
研究领域:
生物催化
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酶工程
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应用微生物学
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制药生物技术
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绿色化学
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DOI
高影响因子
MATERIALS & DESIGN
·
2026
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IF 8.2
Yuman Dong,Jieru Li,Xinyu Zhang,Weihao Jiao,Siyuan Hou,Huiguo Qing,Wentao Zhang,Juanjuan Liu,Pengcheng Du,Zeyuan Yu,Zuoyi Jiao
Redox-responsive ICMNs enable tumor-specific Cu 2+ / Icaritin co-delivery. • Released Icaritin amplifies cuproptosis via ROS generation, and GSH depletion. • ICMNs triggers immunogenic cell death and activates antitumor immunity. • ICMNs inhibits tumor growth, extends survival, and lacks systemic toxicity. Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with limited therapeutic options, largely due to its metabolic adaptability and immunosuppressive tumor microenvironment. Cuproptosis has emerged as a promising therapeutic strategy, however, its efficacy in solid tumors is constrained by intracellular redox buffering and insufficient bioavailable copper. Here, we developed a redox-responsive copper-based nanoplatform (ICMNs) by integrating icaritin (ICA) into a copper metal-organic framework to synergistically induce cuproptosis and immunotherapy. After cell internalization, ICMNs underwent glutathione (GSH)-triggered disassembly, co-releasing Cu 2+ and ICA. Mechanistically, ICMNs elevated intracellular reactive oxygen species levels by ∼ 145-fold while depleted GSH by 56%, thereby amplifying oxidative stress and mitochondrial dysfunction. Furthermore, ICMNs triggered prominent immunogenic cell death, evidenced by a 5.4-fold increase in calreticulin exposure, enhanced HMGB1 release, and ATP secretion, which promoted dendritic cell maturation and CD8 + T-cell activation. In patient-derived organoids, ICMNs reduced organoid viability by over 85%. In PDAC KPC subcutaneous transplant tumor mouse models, ICMNs achieved an 85.6% tumor inhibition rate and significantly prolonged median survival (41.5 vs. 15 days) without obvious systemic toxicity. Collectively, our findings demonstrate that redox potentiates copper-induced tumor cell death and antitumor immunity, offering a promising nanotherapeutic strategy for PDAC treatment. Download: Download high-res image (159KB) Download: Download full-size image
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高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
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IF 8.5
Xuanzuo JIANG,Feifei Feng,Wenyuan JIA,Yuheng YANG,Yongzheng YAN,Zhiqiang CHENG,Yungang LUO,Ji QU,Guomin LIU
Osteoporosis, a systemic bone disease marked by reduced bone mass and deteriorated microstructure, stems primarily from an imbalance between bone formation and resorption. Normally, bone remodeling maintains mass via osteoblast-mediated formation and osteoclast-mediated resorption. In osteoporosis, this balance is disrupted, causing low bone density, increased fragility, higher fracture risk, and pathological bone defects. Current treatments focus on inhibiting resorption (e.g., bisphosphonates, RANKL inhibitors) or promoting formation (e.g., PTH analogues). However, long-term anti-resorptive use risks adverse effects like jaw osteonecrosis or atypical fractures, and drug therapy alone poorly addresses bone defects. Consequently, research increasingly explores natural products (e.g., traditional medicine compounds) and biomaterials for bone regeneration, aiming for safer, more effective therapies. This experiment develops a biomimetic mineralized hydrogel for bone defect implantation. Using carboxymethyl chitosan (CMCS) as the matrix, it cross-links alendronic acid (ALN) with the natural product genipin (GNP), aiming to promote bone regeneration in osteoporotic conditions. This compound is designated ICT@CMCS/ALN.
研究领域:
生物医学工程
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组织工程
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药理学
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生物材料
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骨科
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PubMed
高影响因子
危险品化学品经营许可证（带存储）