RESUMEN
BACKGROUND: Gastric cancer (GC) is difficult to treat with currently available treatments. Securinine (SCR) has a lengthy history of use in the treatment of disorders of the nervous system, and its anticancer potential has been gaining attention in recent years. The aim of this study was to explore the repressive effect of SCR on GC and its fundamental mechanism. METHODS: The efficacy of SCR in GC cells was detected by MTT assays. Colony formation, flow cytometry and Transwell assays were used to assess the changes in the proliferation, apoptosis, cell cycle distribution, migration and invasion of GC cells after treatment. AGS (human gastric carcinoma cell)-derived xenografts were used to observe the effect of SCR on tumor growth in vivo. The molecular mechanism of action of SCR in GC was explored via RNA sequencing, bioinformatics analysis, Western blotting, molecular docking, and immunohistochemistry. RESULTS: SCR was first discovered to inhibit the proliferation, migration, and invasion of GC cells while initiating apoptosis and cell cycle arrest in vitro. It was also established that SCR has excellent anticancer effects in vivo. Interestingly, AURKA acts as a crucial target of SCR, and AURKA expression can be blocked by SCR. Moreover, this study revealed that SCR suppresses the cell cycle and the ß-catenin/Akt/STAT3 pathways, which were previously reported to be regulated by AURKA. CONCLUSION: SCR exerts a notable anticancer effect on GC by targeting AURKA and blocking the cell cycle and ß-catenin/Akt/STAT3 pathway. Thus, SCR is a promising pharmacological option for the treatment of GC.
Asunto(s)
Aurora Quinasa A , Azepinas , Proteínas Proto-Oncogénicas c-akt , Factor de Transcripción STAT3 , Neoplasias Gástricas , beta Catenina , Neoplasias Gástricas/tratamiento farmacológico , Humanos , Factor de Transcripción STAT3/metabolismo , Aurora Quinasa A/metabolismo , Línea Celular Tumoral , Animales , beta Catenina/metabolismo , Azepinas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Compuestos Heterocíclicos de Anillo en Puente/farmacología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Ratones Desnudos , Dioxolanos/farmacología , Ratones Endogámicos BALB C , Ratones , Antineoplásicos Fitogénicos/farmacología , Ciclo Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Carcinogénesis/efectos de los fármacos , Simulación del Acoplamiento Molecular , Lactonas , PiperidinasRESUMEN
BACKGROUND: Spinal Muscular Atrophy (SMA) is a severe motor neuronal disorder with high morbidity and mortality. Securinine has shown the potential to treat SMA; however, its anti-SMA role remains unclear. OBJECTIVE: This study aims to reveal the anti-SMA mechanisms of securinine. METHODS: Securinine-associated targets were acquired from Herbal Ingredients' Targets (HIT), Similarity Ensemble Approach (SEA), and SuperPred. SMA-associated targets were obtained from GeneCards and Dis- GeNET. Protein-protein Interaction (PPI) network was constructed using GeneMANIA, and hug targets were screened using cytoHubba. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using ClusterProfifiler. Molecular docking was conducted using Pymol and Auto- Dock. In vitro assays were used to verify the anti-SMA effects of securinine. RESULTS: Twenty-six intersection targets of securinine and SMA were obtained. HDAC1, HDAC2, TOP2A, PIK3R1, PRMT5, JAK2, HSP90AB1, TERT, PTGS2, and PAX8 were the core targets in PPI network. GO analysis demonstrated that the intersecting targets were implicated in the regulation of proteins, steroid hormones, histone deacetylases, and DNA transcription. KEGG analysis, pathway-pathway, and hub target-pathway networks revealed that securinine might treat SMA through TNF, JAK-STAT, Ras, and PI3K-Akt pathways. Securinine had a favorable binding affinity with HDAC1, HSP90AB, JAK2, PRMT5, PTGS2, and TERT. Securinine rescued viability suppression, mitochondria damage, and SMN loss in the SMA cell model. Furthermore, securinine increased HDAC1 and PRMT5 expression, decreased PTGS2 expression, suppressed the JAK2-STAT3 pathway, and promoted the PI3K-Akt pathway. CONCLUSION: Securinine might alleviate SMA by elevating HDAC1 and PRMT5 expression and reducing PTGS2 via JAK2-STAT3 suppression and PI3K-Akt activation.
Asunto(s)
Atrofia Muscular Espinal , Farmacología en Red , Plantas Medicinales , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/patología , Humanos , Plantas Medicinales/química , Simulación del Acoplamiento Molecular , Azepinas/farmacología , Azepinas/química , Azepinas/aislamiento & purificación , Lactonas/farmacología , Lactonas/química , Lactonas/aislamiento & purificación , Estructura Molecular , Compuestos Heterocíclicos de Anillo en Puente , PiperidinasRESUMEN
Bladder cancer (BC) is the most common malignant tumor in urinary system. Although chemotherapy is one of the most important adjuvant treatments for BC, drug resistance, non-specific toxicity and severe side effects are the major obstacles to BC chemotherapy. Natural products have always been a leading resource of antitumor drug discovery, with the advantages of excellent effectiveness, low toxicity, multi-targeting potency and easy availability. In this study, we evaluated the potential anti-tumor effect of securinine (SEC), a natural alkaloid from Securinega suffruticosa, on BC cells in vitro and in vivo, and delineated the underlying mechanism. We found that SEC inhibited the proliferation, migration and invasion, induced the apoptosis of BC cells in vitro, and retarded the xenograft tumor growth of BC cell in vivo. Notably, SEC had a promising safety profile because it presented no or low toxicity on normal cells and mice. Mechanistically, SEC inactivated Wnt/ß-catenin signaling pathway while activated p38 and JNK signaling pathway. Moreover, ß-catenin overexpression, the p38 inhibitor SB203580 and the JNK inhibitor SP600125 both mitigated the inhibitory effect of SEC on BC cells. Furthermore, we demonstrated a synergistic inhibitory effect of SEC and gemcitabine (GEM) on BC cells in vitro and in vivo. Taken together, our findings suggest that SEC may exert anti-BC cell effect at least through the activation of p38 and JNK signaling pathways, and the inhibition of Wnt/ß-catenin signaling pathway. More meaningfully, the findings indicate that GEM-induced BC cell killing can be enhanced by combining with SEC.
Asunto(s)
Antineoplásicos , Azepinas , Compuestos Heterocíclicos de Anillo en Puente , Lactonas , Piperidinas , Neoplasias de la Vejiga Urinaria , Humanos , Animales , Ratones , Vía de Señalización Wnt , Sistema de Señalización de MAP Quinasas , Proliferación Celular , Antineoplásicos/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Línea Celular Tumoral , beta Catenina/metabolismo , Movimiento Celular , ApoptosisRESUMEN
The microglia, displaying diverse phenotypes, play a significant regulatory role in the development, progression, and prognosis of Parkinson's disease. Research has established that glycolytic reprogramming serves as a critical regulator of inflammation initiation in pro-inflammatory macrophages. Furthermore, the modulation of glycolytic reprogramming has the potential to reverse the polarized state of these macrophages. Previous studies have shown that Levistilide A (LA), a phthalide component derived from Angelica sinensis, possesses a range of pharmacological effects, including anti-inflammatory, antioxidant, and neuroprotective properties. In our study, we have examined the impact of LA on inflammatory cytokines and glucose metabolism in microglia induced by lipopolysaccharide (LPS). Furthermore, we explored the effects of LA on the AMPK/mTOR pathway and assessed its neuroprotective potential both in vitro and in vivo. The findings revealed that LA notably diminished the expression of M1 pro-inflammatory factors induced by LPS in microglia, while leaving M2 anti-inflammatory factor expression unaltered. Additionally, it reduced ROS production and suppressed IκB-α phosphorylation levels as well as NF-κB p65 nuclear translocation. Notably, LA exhibited the ability to reverse microglial glucose metabolism reprogramming and modulate the phosphorylation levels of AMPK/mTOR. In vivo experiments further corroborated these findings, demonstrating that LA mitigated the death of TH-positive dopaminergic neurons and reduced microglia activation in the ventral SNpc brain region of the midbrain and the striatum. In summary, LA exhibited neuroprotective benefits by modulating the polarization state of microglia and altering glucose metabolism, highlighting its therapeutic potential.
Asunto(s)
Compuestos Heterocíclicos de Anillo en Puente , Fármacos Neuroprotectores , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , FN-kappa B/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Microglía , Lipopolisacáridos/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Reprogramación Metabólica , Antiinflamatorios/uso terapéutico , Serina-Treonina Quinasas TOR/metabolismo , Glucosa/metabolismoRESUMEN
The alkaloid securinine was assessed against spore germination of some plant pathogenic and saprophytic fungi (Alternaria alternata, Alternaria brassicae, Alternaria brassicicola, Curvularia lunata, Curvularia maculans, Curvularia pallenscens, Colletotrichum musae, Colletotrichum sp., Erysiphe pisi, Helminthosporium echinoclova, Helminthosporium spiciferum, Heterosporium sp.). Spore germinations of all the tested fungi were inhibited. Alternaria brassicicola, C. lunata, C. pallenscens and H. spiciferum were highly sensitive as complete inhibition of spore germination was observed at very low concentrations (200 ppm).
Asunto(s)
Alternaria , Azepinas , Brassica , Colletotrichum , Hongos , Germinación , Helminthosporium , Compuestos Heterocíclicos de Anillo en Puente , Lactonas , Musa , Phyllanthus , Piperidinas , Plantas , EsporasRESUMEN
<p><b>AIM</b>To study the chemical constituents of the stems and leaves of Aconitum coreanum (Lèvl.) Rapaics.</p><p><b>METHODS</b>The constituents of Aconitum coreanum were isolated by using various kinds of modern chromatographic methods. The new alkaloid was identified on the basis of spectral analysis.</p><p><b>RESULTS</b>Two compounds were isolated and identified as: 13-dehydro-1beta-acetyl-2alpha,6beta-dihydroxyhetisine (I) and Guanfu base G (II).</p><p><b>CONCLUSION</b>Compound I is a new alkaloid.</p>
Asunto(s)
Aconitum , Química , Diterpenos , Compuestos Heterocíclicos de Anillo en Puente , Química , Conformación Molecular , Estructura Molecular , Hojas de la Planta , Química , Tallos de la Planta , Química , Plantas Medicinales , QuímicaRESUMEN
<p><b>AIM</b>To establish a high-performance capillary electrophoresis (HPCE) chiral separation method for d-securinine and l-securinine, and use this method to investigate the stereoselective metabolism process of d- and l-securinine in Wistar rats.</p><p><b>METHODS</b>The electrophoretic condition and parameters were investigated and the optimized conditions were as following: the electrophoretic medium was 40 mmol.L-1 Tris-H3PO4 buffer (pH adjusted to 6.0 with H3PO4) containing 32 mmol.L-1 HP-beta-CD as chiral selector. Determination was carried out with a UV detector at 254 nm. The separations were performed at 16 degrees C with a positive voltage of 15 kV. Samples were injected into the capillary by pressure for 6 s. The biological samples (urine, bile, plasma and feces) of rats were alkalized and extracted with ethyl acetate.</p><p><b>RESULTS</b>The experimental results showed that the concentration of HP-beta-CD, the concentration of the running buffer and the pH value of the buffer were the main important factors which effected the resolution. d-Securinine and l-securinine were separated at baseline level under the determination conditions. The determination was not interfered by endogenous components and metabolites. After i.p. administration, the rats excreted more d-securinine than l-securinine through bile, urine and feces. The metabolism process in rats was stereoselective.</p><p><b>CONCLUSION</b>This method is simple, reliable and suitable for studying the stereoselective metabolism of securinine in rats.</p>
Asunto(s)
Animales , Masculino , Ratas , Alcaloides , Química , Metabolismo , Orina , Azepinas , Química , Metabolismo , Orina , Bilis , Metabolismo , Electroforesis Capilar , Métodos , Euphorbiaceae , Química , Compuestos Heterocíclicos de 4 o más Anillos , Química , Metabolismo , Orina , Compuestos Heterocíclicos de Anillo en Puente , Lactonas , Química , Metabolismo , Orina , Estructura Molecular , Piperidinas , Química , Metabolismo , Orina , Plantas Medicinales , Química , Ratas Wistar , EstereoisomerismoRESUMEN
<p><b>AIM</b>To study the in vitro and in vivo metabolism of (-)-securinine.</p><p><b>METHODS</b>The metabolic transformation of (-)-securinine was studied by using phenobarbital-induced rat liver microsomal incubate containing the NADPH-generating system in vitro and the constitution of the system was optimized. A reversed phase HPLC method was established to analyze the parent drug and its metabolites. The major metabolites were isolated and purified by liquid-liquid extraction, preparative TLC and HPLC, and their structures were elucidated as 6-hydroxyl securinine, 6-carbonyl securinine, 5 beta-hydroxyl securinine and 5 alpha-hydroxyl securinine by 1HNMR, 13CNMR and MS spectral analysis. An HPLC method was developed to analyze securinine and its metabolites in biofluids (bile, urine) of rat. The bile, urine and their enzymatic hydrolyzed samples of the rat i.p. administrated with (-)-securinine were determined by using this method.</p><p><b>RESULTS</b>Four main metabolites of (-)-securinine in rat hepatic microsome incubation were obtained and their structures were elucidated. Metabolites from in vitro study were confirmed in biofluids (bile, urine) which were collected from rats given securinine i.p. It was suggested that 6-hydroxyl securinine was excreted in conjugated form as well by analyzing enzymatic hydrolyzed bile.</p><p><b>CONCLUSION</b>The main metabolic pathway of (-)-securinine in vitro and in vivo is basically elucidated.</p>
Asunto(s)
Animales , Masculino , Ratas , Alcaloides , Metabolismo , Orina , Azepinas , Metabolismo , Orina , Bilis , Metabolismo , Euphorbiaceae , Química , Compuestos Heterocíclicos de 4 o más Anillos , Metabolismo , Orina , Compuestos Heterocíclicos de Anillo en Puente , Técnicas In Vitro , Lactonas , Metabolismo , Orina , Microsomas Hepáticos , Metabolismo , Piperidinas , Metabolismo , Orina , Plantas Medicinales , Química , Ratas Wistar , EstereoisomerismoRESUMEN
This study of the clinical use of nalbuphine as a component of a balanced anesthesia technique was undertaken with the purpose of exploring the feasibility and safety of this drug as well as to establish possible guidelines for its use.