Search Results (39)

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. Full article

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. Full article

Cancer is the leading cause of morbidity and mortality in people throughout the world. There are many signaling pathways associated with cancerous diseases, from which the Mitogen-activated protein kinase (MAPK) pathway performs a significant role in this regard. Apoptosis and proliferation are correlated with MAPK signaling pathways. Plenty of experimental investigations were carried out to assess the role of indole alkaloids in MAPK-mediated cancerous diseases. Previous reports established that indole alkaloids, such as vincristine and evodiamine are useful small molecules in cancer treatment via the MAPK signaling system. Indole alkaloids have the anticancer potential through different pathways. Vincristine and evodiamine are naturally occurring indole alkaloids that have strong anticancer properties. Additionally, much research is ongoing or completed with molecules belonging to this group. The current review aims to evaluate how indole alkaloids affect the MAPK signaling pathway in cancer treatment. Additionally, we focused on the advancement in the role of indole alkaloids, with the intention of modifying the MAPK signaling pathways to investigate potential new anticancer small molecules. Furthermore, clinical trials with indole alkaloids in cancer treatment are also highlighted. Full article

The gut microbiota is a dynamic community of bacteria distributed in the gastroenteric tract and changes in response to diseases, diet, use of antibiotics and probiotics, hygiene status, and other environmental factors. Dysbiosis, a disruption of the normal crosstalk between the host and the microbes, is associated with obesity, diabetes, cancer, and cardiovascular diseases, is linked to a reduction of anti-inflammatory bacteria like Lactobacillus and Roseburia, and to an increase in the growth of proinflammatory species like Ruminococcus gnavus and Bacteroidetes. Some plants possess anticancer properties and various studies have reported that some of these are also able to modulate the gut microbiota. The aim of this work is to evaluate the crucial relationship between medical plants and gut microbiota and the consequences on the onset and progression of cancer. In vivo studies about hematological malignancies showed that beta-glucans tie to endogenous antibeta glucan antibodies and to iC3b, an opsonic fragment of the central complement protein C3, leading to phagocytosis of antibody-targeted neoplastic cells and potentiation of the cytotoxic activity of the innate immune system if administered together with monoclonal antibodies. In conclusion, this review suggests the potential use of medical plants to improve gut dysbiosis and assist in the treatment of cancer. Full article

Being a controller of cytoprotective actions, inflammation, and mitochondrial function through participating in the regulation of multiple genes in response to stress-inducing endogenous or exogenous stressors, the transcription factor Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) is considered the main cellular defense mechanism to maintain redox balance at cellular and tissue level. While a transient activation of NRF2 protects normal cells under oxidative stress, the hyperactivation of NRF2 in cancer cells may help them to survive and to adapt under oxidative stress. This can be detrimental and related to cancer progression and chemotherapy resistance. Therefore, inhibition of NRF2 activity may be an effective approach for sensitizing cancer cells to anticancer therapy. In this review, we examine alkaloids as NRF2 inhibitors from natural origin, their effects on cancer therapy, and/or as sensitizers of cancer cells to anticancer chemotherapeutics, and their potential clinical applications. Alkaloids, as inhibitor of the NRF2/KEAP1 signaling pathway, can have direct (berberine, evodiamine, and diterpenic aconitine types of alkaloids) or indirect (trigonelline) therapeutic/preventive effects. The network linking alkaloid action with oxidative stress and NRF2 modulation may result in an increased NRF2 synthesis, nuclear translocation, as well in a downstream impact on the synthesis of endogenous antioxidants, effects strongly presumed to be the mechanism of action of alkaloids in inducing cancer cell death or promoting sensitivity of cancer cells to chemotherapeutic agents. In this regard, the identification of additional alkaloids targeting the NRF2 pathway is desirable and the information arising from clinical trials will reveal the potential of these compounds as a promising target for anticancer therapy. Full article

The human gut is inhabited by a multitude of bacteria, yeasts, and viruses. A dynamic balance among these microorganisms is associated with the well-being of the human being, and a large body of evidence supports a role of dysbiosis in the pathogenesis of several diseases. Given the importance of the gut microbiota in the preservation of human health, probiotics, prebiotics, synbiotics, and postbiotics have been classically used as strategies to modulate the gut microbiota and achieve beneficial effects for the host. Nonetheless, several molecules not typically included in these categories have demonstrated a role in restoring the equilibrium among the components of the gut microbiota. Among these, rifaximin, as well as other antimicrobial drugs, such as triclosan, or natural compounds (including evodiamine and polyphenols) have common pleiotropic characteristics. On one hand, they suppress the growth of dangerous bacteria while promoting beneficial bacteria in the gut microbiota. On the other hand, they contribute to the regulation of the immune response in the case of dysbiosis by directly influencing the immune system and epithelial cells or by inducing the gut bacteria to produce immune-modulatory compounds, such as short-chain fatty acids. Fecal microbiota transplantation (FMT) has also been investigated as a procedure to restore the equilibrium of the gut microbiota and has shown benefits in many diseases, including inflammatory bowel disease, chronic liver disorders, and extraintestinal autoimmune conditions. One of the most significant limits of the current techniques used to modulate the gut microbiota is the lack of tools that can precisely modulate specific members of complex microbial communities. Novel approaches, including the use of engineered probiotic bacteria or bacteriophage-based therapy, have recently appeared as promising strategies to provide targeted and tailored therapeutic modulation of the gut microbiota, but their role in clinical practice has yet to be clarified. The aim of this review is to discuss the most recently introduced innovations in the field of therapeutic microbiome modulation. Full article

Evodia rutaecarpa (Juss.) Benth is a traditional Chinese medicine. The active ingredient, evodiamine, is a quinolone alkaloid and is found in Evodiae fructus. We investigated the effect of evodiamine on atherosclerosis using LDLR−/− mice fed on a high-fat diet and ox-LDL-induced MOVAS cell lines to construct mouse models and cell-line models. We report a significant reduction in atherosclerotic plaque formation in mice exposed to evodiamine. Our mechanistic studies have revealled that evodiamine can regulate the proliferation, migration, and inflammatory response of and oxidative stress in vascular smooth muscle cells by inhibiting the activation of the PI3K/Akt axis, thus inhibiting the occurrence and development of atherosclerosis. In conclusion, our findings reveal a role for evodiamine in the regulation of vascular smooth muscle cells in atherosclerosis, highlighting a potential future role for the compound as an anti-atherosclerotic agent. Full article

Evodiamine (EVO) exhibits anti-cancer activity through the inhibition of cell proliferation; however, little is known about its underlying mechanism. To determine whether ferroptosis is involved in the therapeutic effects of EVO, we investigated critical factors, such as lipid peroxidation levels and glutathione peroxidase 4 (GPX4) expression, under EVO treatment. Our results showed that EVO inhibited the cell proliferation of poorly differentiated, high-grade bladder cancer TCCSUP cells in a dose- and time-dependent manner. Lipid peroxides were detected by fluorescence microscopy after cancer cell exposure to EVO. GPX4, which catalyzes the conversion of lipid peroxides to prevent cells from undergoing ferroptosis, was decreased dose-dependently by EVO treatment. Given the features of iron dependency and lipid-peroxidation-driven death in ferroptosis, the iron chelator deferoxamine (DFO) was used to suppress EVO-induced ferroptosis. The lipid peroxide level significantly decreased when cells were treated with DFO prior to EVO treatment. DFO also attenuated EVO-induced cell death. Co-treatment with a pan-caspase inhibitor or necroptosis inhibitor with EVO did not alleviate cancer cell death. These results indicate that EVO induces ferroptosis rather than apoptosis or necroptosis. Furthermore, EVO suppressed the migratory ability, decreased the expression of mesenchymal markers, and increased epithelial marker expression, determined by a transwell migration assay and Western blotting. The TCCSUP bladder tumor xenograft tumor model confirmed the effects of EVO on the inhibition of tumor growth and EMT. In conclusion, EVO is a novel inducer for activating the ferroptosis of bladder cancer cells and may be a potential therapeutic agent for bladder cancer. Full article

Alzheimer’s disease is an irreversible neurological disorder for which there are no effective small molecule therapeutics. A phosphodiesterase 5 (PDE5) inhibitor is a candidate medicine for the treatment of Alzheimer’s disease. Rutaecarpine, an indole alkaloid found in Euodiae Fructus, has inhibitory activity for PDE5. Euodiae Fructus contains more evodiamine than rutaecarpine. Therefore, we performed molecular dynamics simulations of the complex of PDE5 and evodiamine. The results showed that the PDE5 and (−)-evodiamine complexes were placed inside the reaction center compared to the case of PDE5 and (+)-evodiamine complex. The binding of (−)-evodiamine to PDE5 increased the root-mean-square deviation and radius of gyration of PDE5. In the PDE5 with (−)-evodiamine complex, the value of the root-mean-square fluctuation of the M-loop, which is thought to be important for activity, increased. This result suggests that (−)-evodiamine may have inhibitory activity. Full article

Evodiamine (EVO) and rutaecarpine (RUT) are the main active compounds of the traditional Chinese medicinal herb Evodia rutaecarpa. Here, we fully optimized the molecular geometries of EVO and RUT at the B3LYP/6-311++G (d, p) level of density functional theory. The natural population analysis (NPA) charges, frontier molecular orbitals, molecular electrostatic potentials, and the chemical reactivity descriptors for EVO and RUT were also investigated. Furthermore, molecular docking, molecular dynamics simulations, and the analysis of the binding free energies of EVO and RUT were carried out against the anticancer target topoisomerase 1 (TOP1) to clarify their anticancer mechanisms. The docking results indicated that they could inhibit TOP1 by intercalating into the cleaved DNA-binding site to form a TOP1–DNA–ligand ternary complex, suggesting that they may be potential TOP1 inhibitors. Molecular dynamics (MD) simulations evaluated the binding stability of the TOP1–DNA–ligand ternary complex. The calculation of binding free energy showed that the binding ability of EVO with TOP1 was stronger than that of RUT. These results elucidated the structure–activity relationship and the antitumor mechanism of EVO and RUT at the molecular level. It is suggested that EVO and RUT may be potential compounds for the development of new anticancer drugs. Full article

Evodiamine isolated from Evodia rutaecarpa has been known to have anti-tumor activity against various cancer cell types. Although there have been reports showing the inhibitory effect of evodiamine on cell survival of gastric cancer cell, it is not clearly explained how evodiamine affects the expression and modification of proteins associated with apoptosis and upstream signal pathways. We confirmed the cytotoxic activity of evodiamine against AGS and MKN45 cells by a WST assay, cell morphological change, and clonogenic assay. The apoptotic cells were evaluated by Annexin V/PI analysis and Western blot and the expressions of apoptosis-related molecules were confirmed by Western blot. Evodiamine promoted apoptosis of AGS gastric cancer cells through both intrinsic and extrinsic signal pathways in a time- and dose-dependent manner. Evodiamine attenuated the expression of anti-apoptotic proteins, including Bcl-2, XIAP, and survivin, and elevated that of the pro-apoptotic protein Bax. Evodiamine also suppressed the FAK/AKT/mTOR signal pathway. Based on these results, we expect that the results from this study will further elucidate our understanding of evodiamine as an anti-cancer drug. Full article

The fruit of Tetradium ruticarpum (TR) is commonly used in Chinese herbal medicine and it has known antiproliferative and antitumor activities, which can serve as a good source of functional ingredients. Although some antiproliferative compounds are reported to be present in TR fruit, most studies only focused on a limited range of metabolites. Therefore, in this study, the antiproliferative activity of different extracts of TR fruit was examined, and the potentially antiproliferative compounds were highlighted by applying an untargeted liquid chromatography–tandem mass spectrometry (LC-MS/MS)-based multi-informative molecular networking strategy. The results showed that among different extracts of TR fruit, the EtOAc fraction F2-3 possessed the most potent antiproliferative activity against HL-60, T24, and LX-2 human cell lines. Through computational tool-aided structure prediction and integrating various data (sample taxonomy, antiproliferative activity, and compound identity) into a molecular network, a total of 11 indole alkaloids and 47 types of quinolone alkaloids were successfully annotated and visualized into three targeted bioactive molecular families. Within these families, up to 25 types of quinolone alkaloids were found that were previously unreported in TR fruit. Four indole alkaloids and five types of quinolone alkaloids were targeted as potentially antiproliferative compounds in the EtOAc fraction F2-3, and three (evodiamine, dehydroevodiamine, and schinifoline) of these targeted alkaloids can serve as marker compounds of F2-3. Evodiamine was verified to be one of the major antiproliferative compounds, and its structural analogues discovered in the molecular network were found to be promising antitumor agents. These results exemplify the application of an LC-MS/MS-based multi-informative molecular networking strategy in the discovery and annotation of bioactive compounds from complex mixtures of potential functional food ingredients. Full article

Liver cancer has relatively few early symptoms and is usually diagnosed in the advanced stage. Sorafenib is the only first-line anticancer drug approved by the Food and Drug Administration (FDA) for advanced HCC; however, its use is limited due to resistance. Therefore, the development of new drugs is essential to achieving customized treatment. Many studies have suggested that Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) is associated with metastasis and cancer formation and progression in various cancers. In the present study, YAP was overexpressed in various patient-derived hepatocarcinoma (HCC) tissues. In addition, this study examined whether evodiamine (which has anticancer effects) can inhibit YAP and, if so, modulate HCC. Evodiamine significantly reduced both the YAP level and cell growth of HCC in a dose-dependent manner. Biochemical analysis indicated mitochondria dysfunction-mediated apoptosis to be the cause of the reduction in HCC cell growth by evodiamine. YAP was overexpressed in metastatic HCC tissues as well when compared to primary HCC tissues. Migration and invasion analysis showed that evodiamine has anti-metastatic ability on Hep3B and Huh-7 cells and reduces the level of vimentin, an EMT marker. In conclusion, YAP is a critical target in HCC therapy, and evodiamine can be an effective HCC anticancer drug by reducing the YAP level. Full article

Obesity is a low-grade systemic inflammatory disease involving adipocytokines. As though Anmyungambi decoction (AMGB) showed significant improvement on obesity in a clinical trial, the molecular mechanism of AMGB in obesity remains unknown. Therefore, we explored the potential mechanisms of action of AMGB on obesity through network pharmacological approaches. We revealed that targets of AMGB are significantly associated with obesity-related and adipocyte-elevated genes. Evodiamine, berberine, genipin, palmitic acid, genistein, and quercetin were shown to regulate adipocytokine signaling pathway proteins which mainly involved tumor necrosis factor receptor 1, leptin receptor. In terms of the regulatory pathway of lipolysis in adipocytes, norephedrine, pseudoephedrine, quercetin, and limonin were shown to affect adrenergic receptor-beta, protein kinase A, etc. We also found that AMGB has the potentials to enhance the insulin signaling pathway thereby preventing type II diabetes mellitus. Additionally, AMGB was discovered to be able to control not only insulin-related proteins but also inflammatory mediators and apoptotic regulators and caspases, hence reducing hepatocyte injury in nonalcoholic fatty liver disease. Our findings help develop a better understanding of how AMGB controls obesity. Full article

Background: Alzheimer’s disease (AD) is the most common neurodegenerative disease, and it manifests as progressive memory loss and cognitive decline. However, there are no effective therapies for AD, which is an urgent problem to solve. Evodiamine, one of the main bioactive ingredients of Evodia rutaecarpa, has been reported to ameliorate blood–brain barrier (BBB) permeability and improve cognitive impairment in ischemia and AD mouse models. However, whether evodiamine alleviates tauopathy remains unclear. This study aimed to examine whether evodiamine ameliorates tau phosphorylation and cognitive deficits in AD models. Methods: A protein phosphatase 2A inhibitor, okadaic acid (OA), was used to induce tau phosphorylation to mimic AD-like models in neuronal cells. Protein expression and cell apoptosis were detected using Western blotting and flow cytometry, respectively. Spatial memory/cognition was assessed using water maze, passive avoidance tests, and magnetic resonance imaging assay in OA-induced mice models, and brain slices were evaluated further by immunohistochemistry. Results: The results showed that evodiamine significantly reduced the expression of phosphor-tau, and further decreased tau aggregation and neuronal cell death in response to OA treatment. This inhibition was found to be via the inhibition of glycogen synthase kinase 3β, cyclin-dependent kinase 5, and mitogen-activated protein kinase pathways. In vivo results indicated that evodiamine treatment ameliorated learning and memory impairments in mice, whereas Western blotting and immunohistochemical analysis of the mouse brain also confirmed the neuroprotective effects of evodiamine. Conclusions: Evodiamine can decrease the neurotoxicity of tau aggregation and exhibit a neuroprotective effect. Our results demonstrate that evodiamine has a therapeutic potential for AD treatment. Full article