Identification of a novel 10-hydroxyevodiamine prodrug as a potent topoisomerase inhibitor with improved aqueous solubility for treatment of hepatocellular carcinoma.

Natural product evodiamine (Evo) and its synthetic derivatives represent an attractive dual Topo 1/2 inhibitors with broad-spectrum antitumor efficacy. However, the clinical applications of these compounds have been impeded by their poor aqueous solubility. Herein, a series of water-soluble 10-substituted-N(14)-phenylevodiamine derivatives were designed and synthesized. The most potent compound 45 featuring a quaternary ammonium salt fragment achieved robust aqueous solubility and nanomolar potency against a panel of human hepatoma cell lines Huh7, HepG2, SK-Hep-1, SMMC-7721, and SMMC-7721/DOX (doxorubicin-resistant cell). Further studies revealed that 45 could inhibit Topo 1 and Topo 2, induce apoptosis, arrest the cell cycle at the G2/M stage and inhibit the migration and invasion. Compound 45 exhibited potent antitumor activity (TGI = 51.1 %, 10 mg/kg) in the Huh7 xenograft model with acceptable safety profile. In addition, a 21-day long-term dose toxicity study confirmed that the maximum tolerated dose of compound 45 was 20 mg/kg. Overall, this study presented a promising Evo-derived candidate for the treatment of hepatocellular carcinoma.

Evodiamine: A Extremely Potential Drug Development Candidate of Alkaloids from Evodia rutaecarpa.

Evodiamine (EVO) is a tryptamine indole alkaloid and the main active ingredient in Evodia rutaecarpa. In recent years, the antitumor, cardioprotective, anti-inflammatory, and anti-Alzheimer's disease effects of EVO have been reported. EVO exerts antitumor effects by inhibiting tumor cell activity and proliferation, blocking the cell cycle, promoting apoptosis and autophagy, and inhibiting the formation of the tumor microvasculature. However, EVO has poor solubility and low bioavailability. Several derivatives with high antitumor activity have been discovered through the structural optimization of EVO, and new drug delivery systems have been developed to improve the solubility and bioavailability of EVO. Current research found that EVO could have toxic effects, such as hepatotoxicity, nephrotoxicity, and cardiac toxicity. This article reviews the pharmacological activity, derivatives, drug delivery systems, toxicity, and pharmacokinetics of EVO and provides research ideas and references for its further in-depth development and clinical applications.

Evodiamine inhibits proliferation and induces apoptosis of nasopharyngeal carcinoma cells via the SRC/ERBB2-mediated MAPK/ERK signaling pathway.

This study aimed to investigate the effect and potential mechanism of evodiamine (EVO) on proliferation and apoptosis of nasopharyngeal carcinoma (NPC) cells. EVO inhibited proliferation, blocked cell cycle progression, and induced apoptosis of NPC cells. There are 27 known anti-NPC targets of EVO, of which eight are core targets, namely SRC, ERBB2, STAT3, MAPK8, NOS3, CXCL8, APP, and HDAC1. Molecular docking analysis showed that the binding of EVO with its key targets (SRC, ERBB2) was good. EVO also reduced the expression of SRC and ERBB2, the key proteins p-MEK and p-ERK1/2 of the MAPK/ERK signaling pathway, and the downstream proteins PCNA and XIAP. EVO inhibited the growth of NPC xenografts in nude mice and reduced the expression levels of SRC, ERBB2, ERK1/2, p-ERK1/2, PCNA and XIAP in NPC tissue. When the MAPK/ERK signaling pathway was activated by epidermal growth factor (EGF), the expression levels of PCNA and XIAP increased, the cell proliferation index increased, and the apoptosis rate decreased in the EGF + EVO treatment group compared to treatment with EVO alone. These changes indicated that the inhibitory effect of EVO on proliferation and apoptosis of NPC cells was related to the down-regulation of SRC and ERBB2 expression, and further inhibition of the MAPK/ERK signaling pathway.

New insights into evodiamine attenuates IPEC-J2 cells pyroptosis induced by T-2 toxin - Activating Keap1-Nrf2/NF-κB signaling pathway through binding with Keap1.

T-2 toxin (T-2) is a highly toxic mycotoxin with a molecular weight of 466.52 g/mol. Evodiamine (EV), an alkaloid component of Evodia, has anti-inflammation and antioxidant properties. As a receptor of oxidative stress, Keap1 with a molecular weight of 70 kDa, is a molecular switch that controls the Nrf2 signaling pathway. In this paper, the effect of EV on Keap1-Nrf2/NF-κB pathway was investigated. Based on our research outcomes, it was observed that T-2 exposure substantially increased IPEC-J2 cells intracellular ROS levels and MDA accumulation, decreased SOD and CAT activities, disrupted intestinal tight junction (ZO-1, occludin, and claudin-1), and up-regulated pyroptosis-related protein (ASC, NLRP3, caspase-1, GSDMD, IL-1ß, and IL-18). Additionally, EV could bind well with Keap1, the separating it from Nrf2, promoting Nrf2 into the nucleus, enhanced antioxidant enzyme activities, reduced the production of ROS, down-regulated NF-κB expression, alleviated T-2-induced pyroptosis, and restored tight junction protein expression. However, after treatment with the Nrf2 inhibitor ML385, ML385 reversed the protective effect of EV on IPEC-J2 cells. Collectively, EV can activate the Keap1-Nrf2/NF-κB signaling pathway via binding to Keap1, exert anti-inflammatory and antioxidant effects, inhibit the pyroptosis of IPEC-J2 cells triggered by T-2, and retore intestinal barrier function.

Evodiamine suppresses endometriosis development induced by early EBV exposure through inhibition of ERß.

Introduction: Endometriosis (EMS) is characterized as a prevalent gynecological inflammatory disorder marked by the existence of endometrial tissues situated beyond the uterus. This condition leads to persistent pelvic pain and may contribute to infertility. In this investigation, we explored the potential mechanism underlying the development of endometriosis (EMS) triggered by transient exposure to either latent membrane protein 1 (LMP1) or Epstein-Barr virus (EBV) in a mouse model. Additionally, we examined the potential inhibitory effect of evodiamine (EDM) on EMS. Methods: Immortalized human endometrial stromal cells (HESC) or epithelial cells (HEEC) were transiently exposed to either EBV or LMP1. The presence of evodiamine (EDM) was assessed for its impact on estrogen receptor ß (ERß) expression, as well as on cell metabolism parameters such as redox balance, mitochondrial function, inflammation, and proliferation. Additionally, a mixture of LMP1-treated HESC and HEEC was administered intraperitoneally to generate an EMS mouse model. Different dosages of EDM were employed for treatment to evaluate its potential suppressive effect on EMS development. Results: Transient exposure to either EBV or LMP1 triggers persistent ERß expression through epigenetic modifications, subsequently modulating related cell metabolism for EMS development. Furthermore, 4.0 µM of EDM can efficiently reverse this effect in in vitro cell culture studies. Additionally, 20 mg/kg body weight of EDM treatment can partly suppress EMS development in the in vivo EMS mouse model. Conclusion: Transient EBV/LMP1 exposure triggers permanent ERß expression, favoring later EMS development, EDM inhibits EMS development through ERß suppression. This presents a novel mechanism for the development of endometriosis (EMS) in adulthood stemming from early Epstein-Barr virus (EBV) exposure during childhood. Moreover, evodiamine (EDM) stands out as a prospective candidate for treating EMS.

A novel derivative of evodiamine improves cognitive impairment and synaptic integrity in AD mice.

Alzheimer's disease (AD), the major cause of dementia, is a multifactoral progressive neurodegenerative disorder that currently affects over 43 million people worldwide. The interaction betweengenetic and environmental factors decides pathogenesis and pathological development. The chemical drugs designed for clinical applications on AD have not reached the expected preventive effect so far.Here, we obtained a new evodiamine (Evo) derivative, LE-42, which exhibited lower cytotoxicity in SH-SY5Y cells and HepaG2 cells than that of Evo. The LD50 of LE-42 in SH-SY5Y cells and HepaG2 cells was increased by 9 folds and 14 folds than Evo, respectively. The LE-42 also exhibited much more potent effects on anti-oxidation and anti-cytotoxicity of AßOs than Evo. The LE-42 significantly improved the working memory, spatial learning, and memory of the 3×Tg AD mice, and the pharmacodynamic dose of LE-42 on AD mice was increased by 500 folds than that of Evo. LE-42 significantly improved the Tau hyperphosphorylation, a typical pathological feature in 3×Tg AD mice. The LE-42 restored the JAK2/STAT3 pathway's dysfunction and upregulated the expression of GluN1, GluA2, SYN, and PSD95, subsequentially improving the synaptic integrity in 3×Tg mice. The activation of the JAK2/STAT3 axis by LE-42 was a possible mechanism for a therapeutic effect on the AD mice.

Inhibitory Effect of Evodiamine on Psoriasis Lesions and Itching in Mice.

Purpose: This study seeks to investigate the effect of evodiamine on psoriasis and psoriatic pruritus. Methods: Imiquimod-induced psoriasiform dermatitis in mice was used as a model, and evodiamine was topically applied for seven days. The mice were observed daily for skin damage on the back, clinical score and their scratching behavior was recorded. Blood samples were collected on the final day of the experiment, and the serum levels of pruritus-associated inflammatory cytokines tumor necrosis factor (TNF) -α, interleukin (IL) -23, and IL-17A were measured using enzyme-linked immunosorbent assay. Histopathological changes were observed in Hematoxylin and Eosin-stained skin specimens. The expression levels of transient receptor potential vanilloid (TRPV) 1, TRPV3, TRPV4, and the pruritus-related mediators Substance P (SP), nerve growth factor (NGF), and calcitonin gene-related peptide (CGRP) in the skin lesions were analyzed using Western blot and qRT-PCR. The effect of evodiamine on the exploratory behavior, motor, and coordination abilities of mice was assessed using open field, suspension, and Rota-Rod experiments. Molecular docking was utilized to verify the binding of evodiamine to the residues of TRPV1, TRPV3, and TRPV4. Results: Evodiamine reduced pruritus and inhibited inflammation by decreasing the levels of inflammatory mediators TNF-α, IL-23, and IL-17A in the serum of Imiquimod-induced mice and attenuated the mRNA and protein expression levels of SP, NGF, CGRP, TRPV1, TRPV3, and TRPV4 in the skin. Conclusion: Evodiamine is an effective treatment for psoriasis and pruritus, due to its ability to inhibit immune inflammation and pruritic mediators.

The Synergistic Anti-tumor Effects of Evodiamine based on Animal Model Experiments: A Systematic Review and Meta-analysis.

BACKGROUND: Evodiamine (EVO) is an alkaloid extracted from the dried and nearly ripe fruits of Euodia rutaecarpa and used as an anti-cancer, anti-inflammatory and anti-obesity agent. However, robust evidence of preclinical experiments has been lacking so far. Therefore, the purpose of this article was to investigate the effect of EVO in combination with other treatments on tumors in animal experiments. METHODS: A systematic review and meta-analysis were conducted to assess the anti-tumor effect of evodiamine-combined therapy. The search engine and electronic databases included PubMed, Scopus, China Knowledge Resource Integrated Database (CNKI), and SinoMed. The research method was based on the PRISMA checklist. RESULTS: A total of 7 studies and 108 animals were included. As a result, EVO combined therapy was found to be more effective than EVO monotherapy. The SMD was -25.64(95% CI: -5.77 -3.13) in tumor growth. In tumor weight, the SMD was -8.91(95% CI: -16.37, -1.44). CONCLUSION: EVO has the potential to alleviate the toxicity of chemotherapeutic agents, which increases the translatability to the clinical situation.

Progress on the effects and underlying mechanisms of evodiamine in digestive system diseases, and its toxicity: A systematic review and meta-analysis.

BACKGROUND: Evodiamine (EVO) is one of the primary components of Evodia rutaecarpa and has been found to have a positive therapeutic effect on various digestive system diseases. However, no systematic review has been conducted on the research progress and mechanisms of EVO in relation to digestive system diseases, and its toxicity. PURPOSE: This study aimed to provide a reference for future research in this field. STUDY DESIGN: A systematic review and meta-analysis of the research progress, mechanisms, and toxicity of EVO in the treatment of digestive system diseases. METHODS: Five electronic databases were utilized to search for relevant experiments. We conducted a comprehensive review and meta-analysis of the pertinent literature following the guidelines of Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA). RESULTS: EVO's animal experiments in digestive system diseases primarily focus on colorectal cancer, gastric ulcers, liver cancer, liver fibrosis, ulcerative colitis, colitis-associated cancer, and functional gastrointestinal disorders. EVO also has positive effects on pancreatic cancer, radiation enteritis, gastric cancer, tongue squamous cancer, hepatitis B, oral cancer, and esophageal cancer in vivo. EVO's in cellular experiments primarily focus on SGC7901, HT29, HCT-116, and HepG2 cells. EVO also exhibits positive effects on SW480, LoVo, BGC-823, AGS, COLO-205, MKN45, SMMC-7721, Bel-7402, QGY7-701, PANC-1, SW1990, BxPC-3, HSC4, MC3, HONE1, and CNE1 cells in vitro. The potential common pathways include TGF-ß, PI3K-AKT, Wnt, ErbB, mTOR, MAPK, HIF-1, NOD-like receptor, NF-κB, VEGF, JAK-STAT, AMPK, Toll-like receptor, EGFR, Ras, TNF, AGE-RAGE, Relaxin, FoxO, IL-17, Hippo, and cAMP. The mechanisms of EVO on ulcerative colitis, gastric cancer, and HCT116 cells are still controversial in vivo. EVO may have a bidirectional regulatory effect on functional gastrointestinal disorders through calcium signaling. The mechanisms of EVO on HCT116, HT29, SW480, AGS, COLO-205, and SW1990 cells are still controversial in vitro. The question of whether EVO has obvious toxicity is controversial. CONCLUSION: In both cellular and animal experiments, EVO has demonstrated positive impacts on digestive system diseases. Nevertheless, additional in vivo and in vitro research is required to confirm the beneficial effects and mechanisms of EVO on digestive system diseases, as well as its potential toxicity.

Nanofiber-based delivery of evodiamine impedes malignant properties of intrahepatic cholangiocarcinoma cells by targeting HDAC4 and restoring TPM1 transcription.

The electrospun nanofiber system is correlated with high efficacy of drug delivery. This study aims to investigate the effect of nanofiber-based delivery of evodiamine, an indole alkaloid derived from Rutaceae plants Evodia rutaecarpa (Juss.) Benth, on intrahepatic cholangiocarcinoma (ICC), as well as to explore the molecular mechanisms. An electrospun nanofiber system carrying evodiamine was generated. Compared to evodiamine treatment alone, the nano-evodiamine exhibited more pronounced effects on suppressing proliferation, colony formation, invasiveness, migration, apoptosis resistance, cell cycle progression, and in vivo tumorigenesis of two ICC cell lines (HUCC-T1 and RBE). ICC cells exhibited increased expression of histone deacetylase 4 (HDAC4) while decreased tropomyosin 1 (TPM1). HDAC4 suppressed TPM1 expression by removing H3K9ac modifications from its promoter. Nano-evodiamine reduced HDAC4 protein levels in ICC cells, thus promoting transcription and expression of TPM1. Either overexpression of HDAC4 or downregulation of TPM1 negated the tumor-suppressive effects of nano-evodiamine. Collectively, this study demonstrates that the electrospun nanofiber system enhances the efficiency of evodiamine. Additionally, evodiamine suppresses the malignant properties of ICC cells. The findings may provide fresh insights into the application of electrospun nanofiber system for drug delivery and the effects of evodiamine on tumor suppression.

Effects of Evodiamine on Behavior and Hippocampal Neurons through Inhibition of Angiotensin-Converting Enzyme and Modulation of the Renin Angiotensin Pathway in a Mouse Model of Post-Traumatic Stress Disorder.

Post-traumatic stress disorder (PTSD) is a persistent psychiatric condition that arises following exposure to traumatic events such as warfare, natural disasters, or other catastrophic incidents, typically characterized by heightened anxiety, depressive symptoms, and cognitive dysfunction. In this study, animals subjected to single prolonged stress (SPS) were administered evodiamine (EVO) and compared to a positive control group receiving sertraline. The animals were then assessed for alterations in anxiety, depression, and cognitive function. Histological analysis was conducted to examine neuronal changes in the hippocampus. In order to predict the core targets and related mechanisms of evodiamine intervention in PTSD, network pharmacology was used. The metabolic markers pre- and post-drug administration were identified using nontargeted serum metabolomics techniques, and the intersecting Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were screened. Finally, the core targets were validated through molecular docking, enzyme-linked immunosorbent assays, and immunofluorescence staining to confirm the anti-PTSD effects and mechanisms of these targets. As well as improving cognitive impairment, evodiamine reversed anxiety- and depression-like behaviors. It also inhibited the reduction in the number of hippocampal neuronal cells and Nissl bodies in SPS mice inhibited angiotensin converting enzyme (ACE) levels in the hippocampus of SPS mice, and modulated the renin angiotensin pathway and its associated serum metabolites in brain tissue. Evodiamine shows promise as a potential candidate for alleviating the symptoms of post-traumatic stress disorder.

Evodiamine encapsulated by hyaluronic acid modified zeolitic imidazolate framework-8 for tumor targeted therapy.

Evodiamine (EVO), a natural bioactive compound extracted from Evodia rutaecarpa, shows therapeutic ability against malignant melanoma. However, the poor solubility and bioavailability of EVO limit its clinical application. Metal-organic frameworks (MOFs) have shown excellent physical and chemical properties and are widely used as drug delivery systems. Among them, zeolitic imidazolate framework-8 (ZIF-8) is a research popular material because of its unique properties, such as hydrothermal stability, non-toxicity, biocompatibility, and pH sensitivity. In this study, in order to load EVO, a drug carrier that hyaluronic acid (HA) modified zeolitic imidazolate framework-8 (ZIF-8) is synthesized. This drug carrier has shown drug loading with 6.2 ± 0.6%, and the nano drugs (EVO@ZIF-8/HA) have good dispersibility. Owing to the decoration HA of EVO@ZIF-8, the potential of the nano drugs is reversed from the positive charge to the negative charge, which is beneficial to blood circulation in vivo. Furthermore, because the CD44-expressing in tumor cells is excessed, the endocytosis and accumulation of nano drugs in tumor cells are beneficial to improvement. Compared with free EVO, EVO@ZIF-8/HA has shown a significantly improved anti-tumor efficacy in vitro and in vivo. In summary, the drug carrier effectively addresses the challenges that are caused by the strong hydrophobicity and low bioavailability of EVO, thereby targeted tumor therapy of EVO can be achieved.

Design, synthesis and biological activity of oxyevodiamine-based histone deacetylase 6 inhibitors.

Histone deacetylase 6 (HDAC6) was a potential target for Alzheimer's disease (AD). In this study, a series of novel oxyevodiamine-based HDAC6 inhibitors with a variety of linker moieties were designed, synthesized and evaluated. Compound 12 with a benzyl linker was identified as a high potent and selective HDAC6 inhibitor. It inhibited HDAC6 with an IC50 value of 6.2 nM and was more than 200 fold selectivity over HDAC1. It also had lower cytotoxicity and higher anti-H2O2 activity in vitro comparing with other derivatives. Compound 12 might be a good lead as novel HDAC6 inhibitor for the treatment of AD.

Maintaining calcium homeostasis as a strategy to alleviate nephrotoxicity caused by evodiamine.

Evodiamine (EVO), the main active alkaloid in Evodia rutaecarpa, was shown to exert various pharmacological activities, especially anti-tumor. Currently, it is considered a potential anti-cancer drug due to its excellent anti-tumor activity, which unfortunately has adverse reactions, such as the risk of liver and kidney injury, when Evodia rutaecarpa containing EVO is used clinically. In the present study, we aim to clarify the potential toxic target organs and toxicity mechanism of EVO, an active monomer in Evodia rutaecarpa, and to develop mitigation strategies for its toxicity mechanism. Transcriptome analysis and related experiments showed that the PI3K/Akt pathway induced by calcium overload was an important step in EVO-induced apoptosis of renal cells. Specifically, intracellular calcium ions were increased, and mitochondrial calcium ions were decreased. In addition, EVO-induced calcium overload was associated with TRPV1 receptor activation. In vivo TRPV1 antagonist and calcium chelator effects were observed to significantly reduce body weight loss and renal damage in mice due to EVO toxicity. The potential nephrotoxicity of EVO was further confirmed by an in vivo test. In conclusion, TRPV1-mediated calcium overload-induced apoptosis is one of the mechanisms contributing to the nephrotoxicity of EVO due to its toxicity, whereas maintaining body calcium homeostasis is an effective measure to reduce toxicity. These studies suggest that the clinical use of EVO-containing herbal medicines should pay due attention to the changes in renal function of patients as well as the off-target effects of the drugs.

Enhancing anticancer treatment: Development of cRGD-Conjugated F-OH-Evo prodrugs for targeted delivery.

Small molecule drugs sourced from natural products are pivotal for novel therapeutic discoveries. However, their clinical deployment is often impeded by non-specific activity and severe adverse effects. This study focused on 3-fluoro-10-hydroxy-Evodiamine (F-OH-Evo), a potent derivative of Evodiamine, whose development is curtailed due to suboptimal tumor selectivity and heightened cytotoxicity. By harnessing the remarkable stability, specificity, and αvß3 integrin affinity of c(RGDFK), a novel prodrug by conjugating F-OH-Evo with cRGD was synthesized. This innovative prodrug substantially enhanced the tumor-specific targeting of F-OH-Evo and improved the anti-tumor activities. Among them, compound 3c demonstrated the best selective inhibitory activity toward U87 cancer cells in vitro. It selectively enterd U87 cells by binding to αvß3 integrin, releasing the parent molecule under the dual response of ROS and GSH to exert inhibitory activity on topo I. The results highlight the potential of cRGD-conjugated prodrugs in targeted cancer therapy. This approach signifies a significant advancement in developing safer and more effective chemotherapy drugs, emphasizing the role of prodrug strategies in overcoming the limitations of traditional cancer treatments.

Metabolic characteristics of evodiamine were associated with its hepatotoxicity via PPAR/PI3K/AKT/NF-кB/tight junction pathway-mediated apoptosis in zebrafish.

Evodiae Fructus (EF), an herbal medicine, possesses remarkable anti-inflammatory and analgesic properties. It exhibits insecticidal activity as a potent insecticide candidate. However, the toxic characteristics of EF and the underlying mechanisms have not been comprehensively elucidated comprehensively. Thus, we comprehensively explored the toxic components of EF and established the relationship between the therapeutic and toxic effects of EF, encouraging its therapeutic use. We found that evodiamine (EVO), one of the main ingredients of EF, can truly reflect its analgesic properties. In phenotype observation trials, low doses of EVO (< 35 ng/mL) exhibited distinct analgesic activity without any adverse effects in zebrafish. However, EVO dose-dependently led to gross morphological abnormalities in the liver, followed by pericardial edema, and increased myocardial concentrations. Furthermore, the toxic effects of EVO decreased after processing in liver microsomes but increased after administering CYP450 inhibitors in zebrafish, highlighting the prominent effect of CYP450s in EVO-mediated hepatotoxicity. EVO significantly changed the expression of genes enriched in multiple pathways and biological processes, including lipid metabolism, inflammatory response, tight junction damage, and cell apoptosis. Importantly, the PPAR/PI3K/AKT/NF-кB/tight junction-mediated apoptosis pathway was confirmed as a critical functional signaling pathway inducing EVO-mediated hepatotoxicity. This study provided a typical example of the overall systematic evaluation of traditional Chinese medicine (TCM) and its active ingredients with significant therapeutic effects and simultaneous toxicities, especially metabolic toxicities.

Experimental and computational study on anti-gastric cancer activity and mechanism of evodiamine derivatives.

Introduction: Human topoisomerase 1 (TOP1) is an important target of various anticancer compounds. The design and discovery of inhibitors targeting TOP1 are of great significance for the development of anticancer drugs. Evodiamine and thieno [2,3-d] pyridine hybrids show potential antitumor activity. Herein, the anti-gastric cancer activities of these hybrids were investigated. Methods: The inhibitory effects of different concentrations of ten evodiamine derivatives on the gastric cancer cell line SGC-7901 were assessed using a methyl thiazolyl tetrazolium assay. Compounds EVO-1 and EVO-6 strongly inhibited gastric cancer cell proliferation, with inhibition rates of 81.17% ± 5.08% and 80.92% ± 2.75%, respectively. To discover the relationship between the structure and activity of these two derivatives, density functional theory was used to investigate their optimized geometries, natural population charges, frontier molecular orbitals, and molecular electrostatic potentials. To clarify their anti-gastric cancer mechanisms, molecular docking, molecular dynamics simulations, and binding free energy calculations were performed against TOP1. Results: The results demonstrated that these compounds could intercalate into the cleaved DNA-binding site to form a TOP1-DNA-ligand ternary complex, and the ligand remained secure at the cleaved DNA-binding site to form a stable ternary complex. As the binding free energy of compound EVO-1 with TOP1 (-38.33 kcal·mol-1) was lower than that of compound EVO-6 (-33.25 kcal·mol-1), compound EVO-1 could be a more potent anti-gastric cancer agent than compound EVO-6. Discussion: Thus, compound EVO-1 could be a promising anti-gastric cancer drug candidate. This study may facilitate the design and development of novel TOP1 inhibitors.

Evodiamine and its nano-based approaches for enhanced cancer therapy: recent advances and challenges.

Evodiamine is a bioactive alkaloid extracted from the Evodia rutaecarpa plant. It has various pharmacological effects including anti-cancer, anti-bacterial, anti-obesity, anti-neurodegenerative, anti-depressant, and cardiac protective properties. Evodiamine demonstrates potent anti-cancer activity by inhibiting the proliferation of cancer cells in vitro and in vivo. Despite the health-promoting properties of evodiamine, its clinical use is hindered by low water solubility, poor bioavailability, and toxicity. Thus, there is a need to develop alternative drug delivery systems for evodiamine to enhance its solubility, permeability, and stability, as well as to facilitate targeted, prolonged, and controlled drug release. Nanocarriers can increase the therapeutic potential of evodiamine in cancer therapy while reducing adverse side effects. To date, numerous attempts have been made through the development of smart nanocarriers to overcome the drawbacks of evodiamine. This review focuses on the pharmacological applications, anti-cancer mechanisms, and limitations of evodiamine. Various nanocarriers, including lipid-based nanoparticles, polymeric nanoparticles, cyclodextrins, and so forth, have been discussed extensively for evodiamine delivery. Nano-drug delivery systems could increase the solubility, bioavailability, stability, and therapeutic efficacy of evodiamine. This review aims to present a comprehensive and critical evaluation of several nano-formulations of evodiamine for cancer therapy. © 2024 Society of Chemical Industry.

Evodiamine Alleviates 2,4-Dinitro-1-Chloro-Benzene-Induced Atopic Dermatitis-like Symptoms in BALB/c Mice.

Evodiamine is an alkaloid found in Evodia fruits, a traditional Chinese medicine. Preclinical studies have demonstrated its anti-inflammatory and neuroprotective properties. The 2,4-dinitro-1-chloro-benzene (DNCB) was used to test the effects of evodiamine on a chemically induced atopic dermatitis-like model in BALB/c mice. Evodiamine significantly lowered serum immunoglobulin E levels, which increased as an immune response to the long-term application of DNCB. Several atopic dermatitis-like skin symptoms induced by DNCB, including skin thickening and mast cell accumulation, were suppressed by evodiamine therapy. DNCB induced higher levels of pro-inflammatory cytokines in type 2 helper T (Th2) cells (IL-4 and IL-13), Th1 cells (IFN-γ and IL-12A), Th17 cells (IL-17A), Th22 cells (IL-22), and chemokines (IL-6 and IL-8). These increases were suppressed in the lymph nodes and skin following evodiamine treatment. The results of our study indicate that evodiamine suppresses atopic dermatitis-like responses in mice and may therefore be useful in treating these conditions.

Evodiamine potentiates cisplatin-induced cell death and overcomes cisplatin resistance in non-small-cell lung cancer by targeting SOX9-ß-catenin axis.

BACKGROUND: In recent decades, phytotherapy has remained as a key therapeutic option for the treatment of various cancers. Evodiamine, an excellent phytocompound from Evodia fructus, exerts anticancer activity in several cancers by modulating drug resistance. However, the role of evodiamine in cisplatin-resistant NSCLC cells is not clear till now. Therefore, we have used evodiamine as a chemosensitizer to overcome cisplatin resistance in NSCLC. METHODS: Here, we looked into SOX9 expression and how it affects the cisplatin sensitivity of cisplatin-resistant NSCLC cells. MTT and clonogenic assays were performed to check the cell proliferation. AO/EtBr and DAPI staining, ROS measurement assay, transfection, Western blot analysis, RT-PCR, Scratch & invasion, and comet assay were done to check the role of evodiamine in cisplatin-resistant NSCLC cells. RESULTS: SOX9 levels were observed to be higher in cisplatin-resistant A549 (A549CR) and NCI-H522 (NCI-H522CR) compared to parental A549 and NCI-H522. It was found that SOX9 promotes cisplatin resistance by regulating ß-catenin. Depletion of SOX9 restores cisplatin sensitivity by decreasing cell proliferation and cell migration and inducing apoptosis in A549CR and NCI-H522CR. After evodiamine treatment, it was revealed that evodiamine increases cisplatin-induced cytotoxicity in A549CR and NCI-H522CR cells through increasing intracellular ROS generation. The combination of both drugs also significantly inhibited cell migration by inhibiting epithelial to mesenchymal transition (EMT). Mechanistic investigation revealed that evodiamine resensitizes cisplatin-resistant cells toward cisplatin by decreasing the expression of SOX9 and ß-catenin. CONCLUSION: The combination of evodiamine and cisplatin may be a novel strategy for combating cisplatin resistance in NSCLC.