PHYTOMEDICINE
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2025
·
IF 8.3
Xiaoyu Tao,Yifei Gao,Zhengsen Jin,Shan Lu,Zhiqi Li,Siyu Guo,Qiqi Fan,Jiaqi Li,Chuanqi Qiao,Huiling Lei,Zhiqiang Zhang,Chongjun Zhao,Jiarui Wu
Background The combined therapeutic mechanisms of evodiamine (EVO) and berberine (BBR), which are the primary bioactive components contributing to the pharmacological effects of Euodiae Fructus and Rhizoma Coptidis , a classic herb pair used for colitis, have not yet been fully elucidated Purpose This study aimed to investigate the critical mechanisms by which co-administration EVO and BBR mitigated EVO-induced hepatotoxicity while exerting therapeutic effects against colitis. Methods Safety and therapeutic outcomes of EVO alone and combined BBR were validated in normal and colitis models. RNA-seq sequencing was performed on liver and colon tissues from different groups, while metagenomic sequencing was utilized to analysis fecal samples. An integrated bioinformatics analysis of transcriptomic and metagenomic data was conducted to reveal the mechanisms underlying EVO-induced hepatotoxicity and the protective and synergistic effects of BBR against colitis. Molecular biology experiments were employed to validate the regulatory mechanism, with a particular emphasis on the interactions within the gut- liver axis, including those related to lipid metabolism and inflammatory pathways. Results BBR attenuated EVO-induced hepatotoxicity in C57 mice by ameliorating pathological injuries and hepatic steatosis as well as inhibiting abnormal AST/ALT elevation, thereby revealing its hepatoprotective effects. In colitis mice, the combination therapy exhibited enhanced efficacy in reducing mucosal damage, restoring goblet cells populations, and suppressing pro-inflammatory cytokines production compared to monotherapy. Integrated analysis of RNA-seq combined with experimental validation revealed that EVO-induced hepatotoxicity was associated with the disrupted fatty acid β-oxidation and cholesterol synthesis homeostasis. Notably, co-administration of BBR effectively rescued metabolic disturbance through modulating core regulatory targets such as ACSL1, CPT1B, SQLE, DHCR7. Additionally, the combination treatment synergistically inhibited IL-17/NF-κB signaling, upregulated tight junction proteins, and rectified gut microbiota dysbiosis, thereby alleviating intestinal injury in colitis mice. Furthermore, ACSL3, a central regulator of fatty acid β-oxidation, was identified as a pivotal target through which the combination of EVO combined BBR suppressed lipid peroxidation-mediated activation of IL-17/NF-κB, leading to alleviate inflammation in LPS-induced NCM460 cell. Conclusion ACSL3 was identified as the critical therapeutic target through underlying the amelioration of fatty acid metabolism-mediated inflammatory injury in colitis by the combined administration of EVO and BBR, thereby offering a scientific foundation for precise and safe clinical drug administration.
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OncoTargets and Therapy
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2022
·
IF 4.345
Rong Wang,Danni Deng,Naiyuan Shao,Yuan Xu,Lian Xue,Ya Peng,Yatian Liu,Feng Zhi
Background Glioblastoma multiforme (GBM) is the most malignant primary tumor of the central nervous system and is associated with a very poor prognosis. No further improvements in outcomes have been reported since radiotherapy-temozolomide therapy was introduced. Therefore, developing new agents to treat GBM is important.Aim This study aimed to evaluate the anti-tumor effect of evodiamine (Evo) on GBM cells, and to determine the underlying mechanisms involved.Results According to MTT assay results, Evo significantly inhibited the cell proliferation in a time- and dose-dependent manner. Fluorescence microscopy and flow cytometry analyses revealed that Evo induced cell apoptosis in a concentration-dependent manner. Moreover, Evo induced reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) disruption. Finally, Evo induced apoptosis in cancer cells by suppressing PI3K/AKT signaling and inducing MAPK phosphorylation (p38 and JNK, but not ERK) to regulate apoptotic proteins (Bax, Bcl-2, Cytochrome c, Caspase-3, and PARP).Conclusion In summary, Evo inhibits cell proliferation by inducing cellular apoptosis via suppressing PI3K/AKT and activating MAPK in GBM; these results indicate that Evo may be regarded as a new approach for GBM treatment.
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Natural Product Communications
·
2022
·
IF 1.496
Ruolan Yang,Jingjing Ma,Hui Guo,Qinghua Meng,Yuwei Wang,Hao Yan,Ruyi Jin,Zhi Li,Lingjie Meng
MS, and IR, 1H NMR and 13C NMR spectroscopy were employed to elucidate 4 novel evodiamine (EVO) derivatives with nitro, amino, and methoxy groups, namely 2-NO2-EVO (7a), 10-OCH3-2-NO2-EVO (7b), 2-NH2-EVO (8a), and 10-OCH3-2-NH2-EVO (8b). The amino compounds (8a, 8b) were obtained by the reduction of nitro derivatives (7a, 7b) with SnCl2/HCl. The antiproliferative activities of these compounds were tested by Cell Counting Kit-8 assay for 48 h against the MDA-MB-231 and sw620 cancer cell lines, as well as the normal LO2 cells. The in vitro experiment showed that 8a possesses the most potent inhibitory activities against MDA-MB-231 and SW620 cells, with IC50 values of 0.79 and 1.28 μM, respectively. The cytotoxicity of 8a against the 2 cancer cell lines was higher than that of EVO.
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PEST MANAGEMENT SCIENCE
·
2025
·
IF 3.8
Wenhao Liang,Xiaoxiao Xu,Tong Shi,Shengyang Xu,Qizhi Wang,Bi Wang
BACKGROUND Phytophthora capsici is a devastating oomycete pathogen with major economic concern. However, the use of traditional chemical fungicides is associated with environmental pollution, and fungicide resistance is increasingly prevalent. Consequently, developing safe, effective, and environmentally friendly alternatives is critically required. Evodiamine (EVO), a bioactive alkaloid from plants, has been extensively investigated for its anti-cancer properties. However, its inhibitory effects against phytopathogens have not yet been fully elucidated. This study evaluated EVO's antimicrobial activity toward P. capsici and its potential mode of action. RESULTS EVO significantly inhibited P. capsici mycelial growth and spore germination, with median effective concentration (EC 50 ) values of 6.48 μg mL −1 and 7.13 μg mL −1 respectively, across 108 P. capsici isolates. EVO exerted its antimicrobial effects by disrupting the cellular integrity of P. capsici , specifically targeting both the cell membrane and wall. Furthermore, EVO exhibited strong protective and curative efficacies in pepper leaves and seedlings. Genome-wide transcriptional analysis revealed that EVO treatment significantly altered the gene expression profile of P. capsici , especially affecting genes relevant to cell membrane integrity and transporter activity. CONCLUSION Overall, this study revealed that EVO showed great control efficacy against P. capsici and held promise as a novel botanical fungicide. © 2025 Society of Chemical Industry.
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MOLECULES
·
2013
·Vol. 18
·期 12
·15750-15768
·
IF 2.428
Senchuan Song,Zhiyong Chen,Shaoxue Li,Yanmin Huang,Yiqian Wan,Huacan Song
Attempting to improve the anticancer activity and solubility of evodiamine in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) solutions, thirty-eight N13-substituted evodiamine derivatives were designed, synthesized and tested for antitumor activities against six kinds of human cancer cell lines, namely prostate cancer (DU-145 and PC-3), lung cancer (H460), breast cancer (MCF-7), colon cancer (HCT-5) and glioblastoma (SF-268). The solubility of these compounds in SGF and SIF solutions was evaluated, and apoptosis induced by2-2,2-3,2-16and3-2was determined. The results showed: (1) among all compounds examined,2-16showed the highest antitumor activity and a broader spectrum of activity, with IC50values ranging from 1–2 µM; (2) their solubility was obviously improved; (3)2-3,2-16and3-2had a significant impact inducing apoptosis in some cancer cell lines. The preliminary structure-activity relationships of these derivatives were discussed.Keywords:N13-substituted evodiamine derivatives;antitumor activity;apoptosis;solubility
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Frontiers in Pharmacology
·
2019
·
IF 3.845
Li Chen-Guang,Zeng Qiong-Zhen,Chen Ming-Ye,Xu Li-Hui,Zhang Cheng-Cheng,Mai Feng-Yi,Zeng Chen-Ying,He Xian-Hui,Ouyang Dong-Yun
Evodiamine is a major ingredient of the plant Evodia rutaecarpa, which has long been used for treating infection-related diseases including diarrhea, beriberi and oral ulcer, but the underlying mechanism is unclear. Here we aimed to explore whether evodiamine influenced NLRP3 (NLR family, pyrin containing domain 3) inflammasome activation in macrophages, which is a critical mechanism for defending the host against pathogenic infections. We uncovered that evodiamine dose-dependently enhanced NLRP3 inflammasome activation in lipopolysaccharide-primed macrophages, as indicated by increased interleukin (IL)-1β production and caspase-1 cleavage, accompanied by increased ASC speck formation and pyroptosis. Mechanistically, evodiamine induced acetylation of α-tubulin around the microtubule organization center (indicated by γ-tubulin) in lipopolysaccharide-primed macrophages. Such evodiamine-mediated increases in NLRP3 activation and pyroptosis were attenuated by activators of α-tubulin deacetylase, resveratrol and NAD+, or dynein-specific inhibitor ciliobrevin A. Small interfering RNA knockdown of αTAT1 (the gene encoding α-tubulin N-acetyltransferase) expression, which reduced α-tubulin acetylation, also diminished evodiamine-mediated augmentation of NLRP3 activation and pyroptosis. Evodiamine also enhanced NLRP3-mediated production of IL-1β and neutrophil recruitment in vivo. Moreover, evodiamine administration evidently improved survival of mice with lethal bacterial infection, accompanied by increased production of IL-1β and interferon-γ, decreased bacterial load, and dampened liver inflammation. Resveratrol treatment reversed evodiamine-induced increases of IL-1β and interferon-γ, and decreased bacterial clearance in mice. Collectively, our results indicated that evodiamine augmented the NLRP3 inflammasome activation through inducing α-tubulin acetylation, thereby conferring intensified innate immunity against bacterial infection.
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COLLOIDS AND SURFACES B-BIOINTERFACES
·
2026
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IF 5.9
Qiuyue Huang,Ruoxuan Xu,Yanchen Liu,Na Li,Yuanyuan Sun,Rongxia Liu
Evo and Cur directly co-assembled into carrier-free nanoparticles • COS@EC NPs prolonged intestinal retention and increased systemic exposure • COS@EC NPs reduced ROS and VSMC proliferation with Nrf2/HO-1 upregulation • CETSA and DARTS supported HO-1 involvement in the cellular response • Oral COS@EC NPs reduced plaque burden in high-fat diet-fed ApoE −/− mice Oxidative stress and dysregulated vascular smooth muscle cell (VSMC) proliferation drive atherosclerotic (AS) progression and plaque development. Natural phytochemicals, including evodiamine (Evo) and curcumin (Cur), show anti-atherosclerotic potential, but poor aqueous solubility and insufficient intestinal absorption limit their oral use. Here, Evo and Cur were co-assembled into carrier-free Evo–Cur nanoparticles (EC NPs) and coated with chitosan oligosaccharide (COS) to obtain COS-coated EC nanoparticles (COS@EC NPs). Spectroscopic analyses and molecular dynamics simulations indicated that hydrophobic interactions, hydrogen bonding, and π–π stacking mediated Evo–Cur nanoassembly. Under simulated gastrointestinal conditions, COS@EC NPs reduced gastric Cur release and increased intestinal Cur release. After oral administration, COS@EC NPs prolonged intestinal residence and increased systemic exposure. In platelet-derived growth factor-BB (PDGF-BB)-stimulated VSMCs, COS@EC NPs suppressed excessive proliferation, reduced intracellular reactive oxygen species (ROS), elevated nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) expression, and restrained cell-cycle progression. This antiproliferative effect was partially reversed by the HO-1 inhibitor zinc protoporphyrin IX, suggesting HO-1 involvement. Cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) analyses showed treatment-associated increases in the apparent thermal and proteolytic stability of HO-1, further supporting its involvement. In high-fat diet-fed ApoE −/− mice, oral administration of COS@EC NPs reduced plaque burden, improved lipid profiles, and alleviated oxidative stress without detectable systemic toxicity. Overall, these findings support COS@EC NPs as a potential carrier-free oral nanomedicine strategy for AS therapy and suggest that HO-1-associated redox regulation contributes to their vascular protective effects.
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JOURNAL OF MEDICINAL CHEMISTRY
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2022
·
IF 8.039
Shanchao Wu,Yahui Huang,Ting Wang,Keliang Li,Junjie Lu,Min Huang,Guoqiang Dong,Chunquan Sheng
On the basis of the synergism of topoisomerase (Top) and histone deacetylase (HDAC) inhibitors in antitumor therapy, a series of novel Top/HDAC dual inhibitors were designed and synthesized by the pharmacophore fusion strategy. After systematic structure–activity relationship studies, lead compound 16j was identified to simultaneously inhibit both Top and HDAC with good potency, which showed potent antiproliferative activities with a broad spectrum. Mechanistic studies indicated that compound 16j efficiently induced apoptosis with S cell-cycle arrest in HEL cancer cells. It was orally active in HEL xenograft models and exhibited excellent in vivo antitumor efficacy (TGI = 68.5%; 10 mg/kg). Altogether, this work highlights the therapeutic potential of evodiamine-inspired Top/HDAC dual inhibitors and provides a valuable lead compound for the development of novel antitumor agents for leukemia therapy.
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INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
·
2025
·Vol. 66
·期 3
·44-44
·
IF 4.7
Boda Li,Junpeng Liu,Di Zhang,Yiran Chu,Zeying Chen,Jiaruei Tsao,Taige Chen,Jiaxuan Jiang,Kai Hu
Purpose:This study aims to explore the therapeutic efficacy of evodiamine (EVO) in the treatment of dry eye disease (DED).Methods:Mouse models of DED was developed using benzalkonium chloride eye drops and subcutaneous atropine injections. Corneal epithelial defects were assessed by fluorescein sodium staining, and tear secretion was measured with the phenol red thread test. For the in vitro model, human corneal epithelial cells were cultured in a sodium chloride–enriched medium. Phenotypic and mechanistic analyses were conducted using real-time quantitative PCR, Western blotting, flow cytometry, and immunofluorescence staining.Results:The administration of EVO eye drops significantly enhanced tear secretion in mice, ameliorated ocular surface damage, decreased the expression of corneal inflammatory factors, and increased the density of conjunctival goblet cells. Furthermore, EVO reduced oxidative stress by promoting autophagy. Mechanistically, EVO-induced autophagy was mediated via the p53/mammalian target of rapamycin pathway.Conclusions:These findings suggest that EVO is a potential therapeutic agent for the treatment of DED, with its beneficial effects attributed to the activation of autophagy through the p53/mammalian target of rapamycin pathway.
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JOURNAL OF PHARMACEUTICAL SCIENCES
·
2026
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IF 3.8
Siyuan Zhao,Chang Chu,Cuiping Li,Qiaoli Zhai,Juan Liu,Huan Sun,Xin Wu,Kourong Shi,Wei Fan
This study aimed to develop a novel peptide–drug conjugate (PDC) by conjugating 3-fluoro-10-hydroxy-evodiamine (FOE) with a bicyclic peptide (BiP) targeting the EphA2 receptor. The goal was to enhance the solubility, tumor selectivity, and therapeutic efficacy of FOE against colorectal cancer (CRC). FOE and BiP were chemically synthesized and coupled through a valine–citrulline cleavable linker to generate BiP–FOE. The compound was structurally characterized, and its solubility, plasma stability, and in vitro cytotoxicity were evaluated in CRC cells. Its effects on cell migration, invasion, apoptosis, and the cell cycle were also assessed. The in vivo targeting ability, antitumor efficacy, and safety were evaluated in an HCT116 xenograft mouse model. BiP–FOE exhibited a greater than 200-fold improvement in aqueous solubility and good metabolic stability. In vitro, BiP–FOE showed selective and potent cytotoxicity toward EphA2-positive HCT116 cells, significantly inhibiting migration and invasion while inducing S-phase arrest and apoptosis. In vivo, BiP–FOE achieved significant accumulation at the tumor site and effectively suppressed tumor growth, with efficacy comparable to or exceeding that of 5-FU. It demonstrated a favorable safety profile, showing minimal body weight loss, negligible hemolysis, and no detectable organ toxicity. BiP–FOE successfully combines the cytotoxic potential of FOE with the tumor-targeting capacity of a bicyclic peptide, resulting in improved solubility, selectivity, efficacy, and safety. These findings highlight BiP–FOE as a promising candidate for targeted CRC therapy and warrant further preclinical development.
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Chemical Biology & Drug Design
·
2023
·Vol. 102
·期 1
·101-114
·
IF 3
Meiya Mao,Xiaojiao Zheng,Yuehua Sheng,Jinghan Chai,Huiqing Ding
Evodiamine (EVO) has been demonstrated to promote apoptosis of ovarian cancer cells, and upregulate miR-152-3p level in colorectal cancer. Here, we explore part of the network mechanism of EVO and miR-152-3p in ovarian cancer. The bioinformatics website, dual luciferase reporter assay, and quantitative real-time polymerase chain reaction were applied to analyze the network among EVO, lncRNA, miR-152-3p, and mRNA. The effect and mechanism of EVO on ovarian cancer cells were determined using cell counting kit-8, flow cytometry, TUNEL, Western blot, and rescue experiments. As a result, EVO dose-dependently attenuated cell viability, induced G2/M phase arrest and apoptosis, promoted miR-152-3p level (4.5- or 2-fold changes), and inhibited expressions of NEAT1 (0.225- or 0.367-fold changes), CDK8 (0.625- or 0.571-fold changes), and CDK19 (0.25- or 0.147-fold changes) in OVCAR-3 and SKOV-3 cells. In addition, EVO decreased Bcl-2 expression, but increased the expressions of Bax and c-caspase-3. NEAT1 targeted miR-152-3p which bound to CDK19. The impacts of EVO on cell viability, cycle, apoptosis, and apoptosis-related proteins were partially reversed by miR-152-3p inhibitor, NEAT1 overexpression, or CDK19 overexpression. Furthermore, miR-152-3p mimic offset the effects of NEAT1 or CDK19 overexpression. The role of NEAT1 overexpression in the biological phenotype of ovarian cancer cells was counteracted by shCDK19. In conclusion, EVO attenuates ovarian cancer cell progression via the NEAT1-miR-152-3p-CDK19 axis.
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JOURNAL OF MOLECULAR HISTOLOGY
·
2025
·Vol. 56
·期 6
·1-14
·
IF 2.2
Wang Pu,Sun Congcong,Shi Chao,Gao Yong,Luan Chunyu,Yan Chao
Osteoarthritis (OA) is a degenerative joint disease characterized by pathological changes such as articular cartilage degeneration and bone hyperplasia. Mitochondrial dysfunction in chondrocytes has been identified as a critical factor contributing to the progression of OA. Although Evodiamine (Evo) has been demonstrated effeicacy in inhibiting inflammatory responses and matrix degradation in OA chondrocytes, its effects and underlying mechanisms regarding mitochondrial dysfunction in these cells remain to be elucidated. IL-1β was utilized to stimulate chondrocytes in order to establish an in vitro OA model. Subsequently, the proliferation, lactate dehydrogenase (LDH) release, and apoptosis of chondrocytes were systematically evaluated. Mitochondrial function in chondrocytes was evaluated by quantifying of ATP content, ROS level, mitochondrial DNA (mtDNA) copy number, activities of mitochondrial respiratory chain Complexes I and III, as well as mitochondrial membrane potential change. Furthermore, the protein expression levels of the SIRT1/PGC-1α signaling pathway were examined, and an intervention involving the SIRT1 inhibitor EX527 was conducted to elucidate the potential mechanisms underlying the effects of Evo on chondrocytes. Evo treatment significantly elevated the proliferation activity of IL-1β-stimulated chondrocytes, inhibited LDH release and apoptosis, increased mtDNA copy number and ATP content, enhanced the enzymatic activities of Complexes I and III, and suppressed ROS production as well as mitochondrial membrane potential loss. Furthermore, Evo treatment activated the SIRT1/PGC-1α signaling pathway. However, the addition of the SIRT1 inhibitor EX-527 partially attenuated the protective effects of Evo against IL-1β-induced chondrocyte injury by exacerbating mitochondrial dysfunction. Evo promotes mitochondrial biosynthesis, reduces ROS production and improves mitochondrial function by activating SIRT1/PGC-1α pathway, thereby inhibiting IL-1β-induced chondrocyte injury.
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