RESUMEN

OBJECTIVE: To investigate the effect of sanguinarine (SAN) on proliferation and ferroptosis of colorectal cancer cells. METHODS: SW620 and HCT-116 cells treated with different concentrations of SAN were examined for cell viability changes using CCK8 assay to determine the IC50 of SAN in the two cells. The inhibitory effects of SAN on proliferation, invasion and migration of the cells were evaluated using colony-forming assay and Transwell assays. ROS production in the treated cells was analyzed with flow cytometry, and lipid peroxide production was assessed by detecting malondialdehyde (MDA) level. Glutathione (GSH) levels in the cells were detected, and Western blotting was used to detect the expressions of ferroptosis-related proteins STUB1 and GPX4. RESULTS: SAN significantly inhibited the proliferation, invasion and migration of SW620 and HCT-116 cells. SAN treatment significantly promoted ROS production, increased intracellular MDA level, and lowered GSH level in the two cells (P<0.05). Western blotting showed that SAN significantly upregulated the expression of STUB1 and down-regulated the expression of its downstream protein GPX4 (P<0.05). CONCLUSION: SAN induces ferroptosis in colorectal cancer cells by regulating STUB1/GPX4, which may serve as a new therapeutic target for colorectal cancer.

Asunto(s)

Benzofenantridinas , Proliferación Celular , Neoplasias Colorrectales , Ferroptosis , Isoquinolinas , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Humanos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Ferroptosis/efectos de los fármacos , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Proliferación Celular/efectos de los fármacos , Isoquinolinas/farmacología , Línea Celular Tumoral , Benzofenantridinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Regulación hacia Abajo , Células HCT116 , Regulación hacia Arriba/efectos de los fármacos , Movimiento Celular/efectos de los fármacos

RESUMEN

The rising incidence of colorectal cancer (CRC) and gastric cancer (GC) worldwide, coupled with the limited effectiveness of current chemotherapeutic agents, has prioritized the search for new therapeutic options. Natural substances, which often exhibit cytostatic properties, hold significant promise in this area. This review evaluates the anticancer properties of three natural alkaloids-berberine, sanguinarine, and chelerythrine-against CRC and GC. In vivo and in vitro studies have demonstrated that these substances can reduce tumor volume and inhibit the epithelial-mesenchymal transition (EMT) of tumors. At the molecular level, these alkaloids disrupt key signaling pathways in cancer cells, including mTOR, MAPK, EGFR, PI3K/AKT, and NF-κB. Additionally, they exhibit immunomodulatory effects, leading to the induction of programmed cell death through both apoptosis and autophagy. Notably, these substances have shown synergistic effects when combined with classical cytostatic agents such as cyclophosphamide, 5-fluorouracil, cetuximab, and erlotinib. Furthermore, berberine has demonstrated the ability to restore sensitivity in individuals originally resistant to cisplatin GC. Given these findings, natural compounds emerge as a promising option in the chemotherapy of malignant gastrointestinal tumors, particularly in cases with limited treatment options. However, more research is necessary to fully understand their therapeutic potential.

Asunto(s)

Benzofenantridinas , Berberina , Neoplasias Colorrectales , Neoplasias Gástricas , Humanos , Benzofenantridinas/farmacología , Benzofenantridinas/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Berberina/farmacología , Berberina/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Animales , Isoquinolinas/farmacología , Isoquinolinas/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Alcaloides/farmacología , Alcaloides/uso terapéutico

RESUMEN

Forest frog's oviduct oil (FFOO) is highly susceptible to microbial spoilage during storage, which causes serious safety concerns and economic losses. However, little information is available regarding the preservation of it up to now. The aim of this research is to understand the dominant microbial community of FFOO spoilage, and based on this, develop a kind of edible nanoemulsion coating for preserving FFOO. Microbial metagenomic analysis indicated that the Aspergillus genus increased significantly during storage. In the present study, gum arabic and whey protein isolate were chosen as the coating matrix, the natural compounds sanguinarine and glabridin were selected as antimicrobial agents to prepare double-layer nanoemulsion edible coating. When the ratio of sanguinarine and glabridin in the nanoemulsion was 1:3, it exhibited strongest storage stability and antifungal activity. The mycelial inhibition rate of 1:3 nanoemulsion against dominant microbial community (Aspergillus niger and Aspergillus glaucus) reached 88.89 ± 1.37 % and 89.68 ± 1.37 %, respectively. The experimental results indicated that the edible nanoemulsion coating not only had outstanding antifungal activity, but also had excellent fresh-keeping effect on FFOO. This nanoemulsion coating could be a promising and potential candidate for food preservation.

Asunto(s)

Antifúngicos , Emulsiones , Goma Arábiga , Animales , Antifúngicos/farmacología , Antifúngicos/química , Femenino , Goma Arábiga/química , Benzofenantridinas/química , Benzofenantridinas/farmacología , Proteína de Suero de Leche/química , Proteína de Suero de Leche/farmacología , Pruebas de Sensibilidad Microbiana , Isoquinolinas

RESUMEN

Vancomycin-resistant enterococcus (VRE) is a major nosocomial pathogen that exhibits enhanced infectivity due to its robust virulence and biofilm-forming capabilities. In this study, 6-methoxyldihydrochelerythrine chloride (6-MDC) inhibited the growth of exponential-phase VRE and restored VRE's sensitivity to vancomycin. 6-MDC predominantly suppressed the de novo biosynthetic pathway of pyrimidine and purine in VRE by the RNA-Seq analysis, resulting in obstructed DNA synthesis, which subsequently weakened bacterial virulence and impeded intracellular survival. Furthermore, 6-MDC inhibited biofilm formation, eradicated established biofilms, reduced virulence, and enhanced the host immune response to prevent intracellular survival and replication of VRE. Finally, 6-MDC reduced the VRE load in peritoneal fluid and cells significantly in a murine peritoneal infection model. This paper provides insight into the potential antimicrobial target of benzophenanthridine alkaloids for the first time.

Asunto(s)

Antibacterianos , Benzofenantridinas , Biopelículas , Pruebas de Sensibilidad Microbiana , Enterococos Resistentes a la Vancomicina , Animales , Ratones , Antibacterianos/farmacología , Antibacterianos/química , Benzofenantridinas/farmacología , Benzofenantridinas/química , Enterococos Resistentes a la Vancomicina/efectos de los fármacos , Biopelículas/efectos de los fármacos , Virulencia/efectos de los fármacos , Vancomicina/farmacología , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/microbiología , Humanos , Femenino

RESUMEN

Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS), two prominent per- and polyfluoroalkyl substances (PFASs), are potentially harmful to many human organs. However, there only exist limited methods to mitigate their health hazards. The aim of this study is to combine a bioinformatics analysis with in vitro experiments to discover small molecules that can alleviate liver damage caused by PFOA/PFOS. We identified 192 and 82 key genes related to hepatocytes exposed to PFOA and PFOS, respectively. The functional enrichment analysis of key genes suggested cellular senescence may be important in PFOA/PFOS-induced hepatotoxicity. The in vitro models revealed that PFOA/PFOS led to hepatocyte senescence by increasing the activity of SA-ß-gal, inducing mitochondrial dysfunction, impacting cell cycle arrest, and elevating the expressions of p21, p53, IL-1ß, and SASP-related cytokines. The drug-target gene set enrichment analysis method was employed to compare the transcriptome data from the Gene Expression Omnibus database (GEO), Comparative Toxicogenomics Database (CTD), and the high-throughput experiment- and reference-guided database (HERB), and 21 traditional Chinese medicines (TCMs) were identified that may alleviate PFOA/PFOS-induced liver aging. The experimental results of co-exposure to PFOA/PFOS and TCMs showed that sanguinarine has particular promise in alleviating cellular senescence caused by PFOA/PFOS. Further investigations revealed that the mTOR-p53 signaling pathway was involved in PFOA/PFOS-mediated hepatic senescence and can be blocked using sanguinarine.

Asunto(s)

Ácidos Alcanesulfónicos , Caprilatos , Senescencia Celular , Fluorocarburos , Hepatocitos , Isoquinolinas , Fluorocarburos/toxicidad , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Senescencia Celular/efectos de los fármacos , Caprilatos/toxicidad , Humanos , Ácidos Alcanesulfónicos/toxicidad , Isoquinolinas/farmacología , Benzofenantridinas/farmacología , Biología Computacional , Animales , Células Hep G2 , Transducción de Señal/efectos de los fármacos

RESUMEN

PURPOSE: Aspergillus fumigatus (A. fumigatus) keratitis is a type of infectious corneal disease that significantly impairs vision. The objective of this study is to evaluate the therapeutic potential of chelerythrine (CHE) on A. fumigatus keratitis. METHODS: The antifungal activity of CHE was assessed through various tests including the minimum inhibitory concentration test, scanning electron microscopy, transmission electron microscopy, propidium iodide uptake test and plate count. Neutrophil infiltration and activity were assessed using immunofluorescence staining and the myeloperoxidase test. RT-PCR, western blotting assay, and ELISA were performed to measure the expression levels of proinflammatory cytokines (IL-1ß and IL-6), NF-E2-related factor (Nrf2), heme oxygenase-1 (HO-1), and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), as well as to determine the ratio of phosphorylated-p38 (p-p38) mitogen-activated protein kinase (MAPK) to p38 MAPK. RESULTS: In vitro, CHE inhibited the growth of A. fumigatus conidia, reduced fungal hyphae survival, and prevented fungal biofilm formation. In vivo, CHE reduced the severity of A. fumigatus keratitis and exhibited an excellent anti-inflammatory effect by blocking neutrophil infiltration. Furthermore, CHE decreased the expression levels of proinflammatory cytokines and LOX-1 at both mRNA and protein levels, while also decreasing the p-p38 MAPK/p38 MAPK ratio. Additionally, CHE increased the expression levels of Nrf2 and HO-1. CONCLUSION: CHE provides protection against A. fumigatus keratitis through multiple mechanisms, including reducing fungal survival, inducing anti-inflammatory effects, enhancing Nrf2 and HO-1 expression, and suppressing the signaling pathway of LOX-1/p38 MAPK.

Asunto(s)

Aspergilosis , Aspergillus fumigatus , Benzofenantridinas , Queratitis , Factor 2 Relacionado con NF-E2 , Receptores Depuradores de Clase E , Proteínas Quinasas p38 Activadas por Mitógenos , Aspergillus fumigatus/efectos de los fármacos , Receptores Depuradores de Clase E/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Queratitis/microbiología , Queratitis/tratamiento farmacológico , Queratitis/metabolismo , Animales , Benzofenantridinas/farmacología , Benzofenantridinas/uso terapéutico , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Aspergilosis/tratamiento farmacológico , Aspergilosis/microbiología , Hemo-Oxigenasa 1/metabolismo , Transducción de Señal/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Femenino , Citocinas/metabolismo

RESUMEN

The novel bactericidal target-filamentous temperature-sensitive protein Z (FtsZ)-has drawn the attention of pharmacologists to address the emerging issues with drug/pesticide resistance caused by pathogenic bacteria. To enrich the structural diversity of FtsZ inhibitors, the antibacterial activity and structure-activity relationship (SAR) of natural sanguinarine and its analogs were investigated by using natural-products repurposing strategy. Notably, sanguinarine and chelerythrine exerted potent anti-Xanthomonas oryzae pv. oryzae (Xoo) activity, with EC50 values of 0.96 and 0.93 mg L-1, respectively, among these molecules. Furthermore, these two compounds could inhibit the GTPase activity of XooFtsZ, with IC50 values of 241.49 µM and 283.14 µM, respectively. An array of bioassays including transmission electron microscopy (TEM), fluorescence titration, and Fourier transform infrared spectroscopy (FT-IR) co-verified that sanguinarine and chelerythrine were potential XooFtsZ inhibitors that could interfere with the assembly of FtsZ filaments by inhibiting the GTPase hydrolytic ability of XooFtsZ protein. Additionally, the pot experiment suggested that chelerythrine and sanguinarine demonstrated excellent curative activity with values of 59.52% and 54.76%, respectively. Excitedly, these two natural compounds also showed outstanding druggability, validated by acceptable drug-like properties and low toxicity on rice. Overall, the results suggested that chelerythrine was a new and potential XooFtsZ inhibitor to develop new bactericide and provided important guiding values for rational drug design of FtsZ inhibitors. Notably, our findings provide a novel strategy to discover novel, promising and green bacterial compounds for the management of plant bacterial diseases.

Asunto(s)

Antibacterianos , Proteínas Bacterianas , Benzofenantridinas , Proteínas del Citoesqueleto , Isoquinolinas , Xanthomonas , Benzofenantridinas/farmacología , Benzofenantridinas/química , Antibacterianos/farmacología , Antibacterianos/química , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Relación Estructura-Actividad , Isoquinolinas/farmacología , Isoquinolinas/química , Proteínas del Citoesqueleto/antagonistas & inhibidores , Proteínas del Citoesqueleto/metabolismo , Xanthomonas/efectos de los fármacos , Productos Biológicos/farmacología , Productos Biológicos/química , Pruebas de Sensibilidad Microbiana

RESUMEN

AIMS: Nitidine chloride (NC), a natural phytochemical alkaloid derived from Zanthoxylum nitidum (Roxb.) DC, exhibits multiple bioactivities, including antitumor, anti-inflammatory, and other therapeutic effects. However, the primary targets of NC and the mechanism of action (MOA) have not been explicitly defined. METHODS: We explored the effects of NC on mTORC1 signaling by immunoblotting and fluorescence microscopy in wild-type and gene knockout cell lines generated by the CRISPR/Cas9 gene editing technique. We identified IGF2R as a direct target of NC via the drug affinity-responsive target stability (DARTS) method. We investigated the antitumor effects of NC using a mouse melanoma B16 tumor xenograft model. KEY FINDINGS: NC inhibits mTORC1 activity by targeting amino acid-sensing signaling through activating transcription factor 4 (ATF4)-mediated Sestrin2 induction. NC directly binds to IGF2R and promotes its lysosomal degradation. Moreover, NC displayed potent cytotoxicity against various cancer cells and inhibited B16 tumor xenografts. SIGNIFICANCE: NC inhibits mTORC1 signaling through nutrient sensing and directly targets IGF2R for lysosomal degradation, providing mechanistic insights into the MOA of NC.

Asunto(s)

Factor de Transcripción Activador 4 , Benzofenantridinas , Lisosomas , Diana Mecanicista del Complejo 1 de la Rapamicina , Transducción de Señal , Animales , Ratones , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Factor de Transcripción Activador 4/metabolismo , Factor de Transcripción Activador 4/genética , Transducción de Señal/efectos de los fármacos , Humanos , Lisosomas/metabolismo , Lisosomas/efectos de los fármacos , Benzofenantridinas/farmacología , Ratones Endogámicos C57BL , Línea Celular Tumoral , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Sestrinas

RESUMEN

Dietary Macleaya cordata extract (MCE) can improve the meat quality of poultry. However, the specific mechanism by which MCE regulates the meat quality has not been clarified yet. Sanguinarine (SAN) is one of the important natural active components in MCE. Our study aims to explore the regulatory mechanism of dietary SAN supplementation on meat quality through transcriptomic and gut microbiome analysis, thereby providing a basis for regularing meat quality with MCE. 240 1-day-old broilers were divided into 4 groups according to different doses of SAN (0, 0.225, 0.75, and 2.25 mg/kg). The results indicated that SAN significantly improve the physicochemical quality indicators of breast and thigh muscle in broilers, improved the serum biochemical indexes. Through transcriptome sequencing analysis of the liver and ileum tissues of broilers, we found that the differentially expressed genes induced by SAN were mainly enriched in lipid metabolism, which were related to the peroxisome proliferator-activated receptor (PPAR) pathway. It reconfirmed that SAN can regulate lipid metabolism in the body by promoting the expression of genes related to cholesterol metabolism, fatty acid transport and oxidation by RT-PCR, this ultimately affects the physicochemical quality of muscle. Additionally, through 16S rRNA sequencing analysis, we found that dietary addition of SAN increased the relative abundance of Bacteroides, Lactobacillus and unclassified_f_Lachnospiraceae, while decreased the relative abundance of Alistipes in ceca. To further investigate the impact of gut microbiota on lipid metabolism, we conducted a correlation analysis of PPAR pathway factor expression in cecum tissue and microflora structure. The results showed that Bacteroides exhibited a positive correlation with the expression of most genes in the PPAR signaling pathway. Unclassified_f__Lachnospiraceae is positively correlated with PPARγ, Cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and Acyl-CoA synthetase long-chain family member 5 (ACSL5). In conclusion, dietary addition of SAN can promote the genes expression of the PPAR pathway, target the regulation of intestinal microflora structure and abundance and regulate lipid metabolism, thereby improving meat quality of broilers.

Asunto(s)

Alimentación Animal , Benzofenantridinas , Pollos , Dieta , Suplementos Dietéticos , Microbioma Gastrointestinal , Isoquinolinas , Metabolismo de los Lípidos , Carne , Animales , Pollos/fisiología , Alimentación Animal/análisis , Metabolismo de los Lípidos/efectos de los fármacos , Dieta/veterinaria , Benzofenantridinas/administración & dosificación , Benzofenantridinas/farmacología , Suplementos Dietéticos/análisis , Microbioma Gastrointestinal/efectos de los fármacos , Isoquinolinas/administración & dosificación , Isoquinolinas/farmacología , Carne/análisis , Relación Dosis-Respuesta a Droga , Papaveraceae/química , Distribución Aleatoria , Masculino , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacología , Extractos Vegetales/química

RESUMEN

Three previously undescribed and sixteen known alkaloids were bioguidedly isolated from the bulbs of Narcissus tazetta subsp. chinensis (M.Roem.) Masamura & Yanagih. The structures were elucidated by spectroscopic data, including HRESIMS, NMR, and ECD. Eleven of the isolated alkaloids exhibited immunosuppressive activity on the proliferation of human T cells. (+)-Narciclasine (18) showed the most significantly suppressive activity with an IC50 value of 14 ± 5 nM. In vitro, (+)-narciclasine (18) blocked NF-κB signal transduction, but did not affect PI3K/AKT signal transduction. What was more, (+)-narciclasine significantly reduced ALT and AST levels and alleviated liver damage induced by ConA in AIH mouse model.

Asunto(s)

Alcaloides , Proliferación Celular , Inmunosupresores , Narcissus , Narcissus/química , Humanos , Animales , Alcaloides/farmacología , Alcaloides/química , Alcaloides/aislamiento & purificación , Inmunosupresores/farmacología , Inmunosupresores/química , Inmunosupresores/aislamiento & purificación , Ratones , Proliferación Celular/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Estructura Molecular , FN-kappa B/metabolismo , FN-kappa B/antagonistas & inhibidores , Benzofenantridinas/farmacología , Benzofenantridinas/química , Benzofenantridinas/aislamiento & purificación , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga , Estereoisomerismo , Transducción de Señal/efectos de los fármacos , Fenantridinas , Alcaloides de Amaryllidaceae

RESUMEN

The nanomaterialization of traditional Chinese medicine (TCM) has aroused widespread interest among researchers. Sanguinarine (SAN) is a kind of TCM with good antibacterial properties, which has important applications in anti-infection of wounds. Additionally, the combination of photothermal therapy and chemotherapy can overcome bacterial resistance, further improving bactericidal and wound healing efficiency. In this paper, we prepared an antibacterial agent by loading SAN on the zwitterion-modified MXene quantum dot nanocarrier (SAN@AHEP@Ta4C3), realizing pH/NIR controlled drug release and photothermal/chemotherapy synergistic antibacterial and wound healing. The particle size of SAN@AHEP@Ta4C3 is about 120 nm, and it has a good water solubility and stability. In addition, it also has excellent photothermal conversion performance (η = 39.2%), which can effectively convert light energy into heat energy under near-infrared (NIR) laser irradiation, further promoting drug release and achieving bactericidal effects by synergistic chemotherapy and photothermal therapy. The in vitro and in vivo experiments show that SAN@AHEP@Ta4C3 exhibits an excellent antibacterial effect against Staphylococcus aureus and Escherichia coli, and it can effectively promote the wound healing of mice. Moreover, the SAN@AHEP@Ta4C3 also has good biocompatibility and has no side effects on normal tissue and organs. This work introduces a multifunctional antibacterial agent based on TCM and hot-spot material MXene, which will have considerable application prospects in biomedical fields.

Asunto(s)

Antibacterianos , Benzofenantridinas , Portadores de Fármacos , Escherichia coli , Isoquinolinas , Puntos Cuánticos , Staphylococcus aureus , Cicatrización de Heridas , Antibacterianos/farmacología , Antibacterianos/química , Cicatrización de Heridas/efectos de los fármacos , Puntos Cuánticos/química , Staphylococcus aureus/efectos de los fármacos , Animales , Benzofenantridinas/química , Benzofenantridinas/farmacología , Escherichia coli/efectos de los fármacos , Ratones , Portadores de Fármacos/química , Isoquinolinas/química , Isoquinolinas/farmacología , Medicina Tradicional China , Terapia Fototérmica , Liberación de Fármacos , Pruebas de Sensibilidad Microbiana

RESUMEN

Osteoarthritis is a highly prevalent joint disease; however, effective treatments are lacking. Protopine (PTP) is an isoquinoline alkaloid with potent anti-inflammatory and antioxidant properties; however, it has not been studied in osteoarthritis. This study aimed to investigate whether PTP can effectively protect chondrocytes from ferroptosis. Primary mouse chondrocytes were treated with tert-butyl hydroperoxide (TBHP) to simulate oxidative stress in an in vitro model of osteoarthritis. Two concentrations of PTP (10 and 20 µg/mL) were validated for in vitro experiments. Cellular inflammation and metabolism were detected using RT-qPCR and western blotting (WB). Ferroptosis was assessed via WB, qPCR, reactive oxygen species (ROS) levels, lipid ROS, and immunofluorescence staining. In vitro, PTP significantly ameliorated chondrocyte inflammation and cytolytic metabolism and significantly suppressed chondrocyte ferroptosis through the activation of the Nrf2 pathway. The anterior cruciate ligament transection (ACLT) mouse model was used to validate the in vivo effects of PTP. The joint cartilage was assessed using the Osteoarthritis Research Society International (OARSI) score, Safranin O staining, and immunohistochemistry. The intra-articular administration of PTP alleviated cartilage inflammation and ferroptosis, as evidenced by the expression of MMP3, MMP13, COL2A1, GPX4, and Nrf2. Overall, we find that PTP exerted anti-ferroptosis and anti-inflammatory effects on chondrocytes to protect the articular cartilage.

Asunto(s)

Benzofenantridinas , Alcaloides de Berberina , Ferroptosis , Osteoartritis , Animales , Ratones , Antiinflamatorios/farmacología , Benzofenantridinas/farmacología , Alcaloides de Berberina/farmacología , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Ferroptosis/efectos de los fármacos , Inflamación/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Osteoartritis/patología , Especies Reactivas de Oxígeno/metabolismo

RESUMEN

Ovarian cancer is a prevalent malignancy in the female reproductive system, representing a significantly fatal and incurable tumor. Chelerythrine (CHE), a natural benzopyridine alkaloid, has demonstrated a broad spectrum of anticancer activities. Nevertheless, the ovarian cancer inhibitory impact of CHE remains unclear. In this study, we investigated the cytotoxic mechanism and potential targets of CHE on in vitro cultures of A2780 and SKOV3 cells derived from ovarian cancer. Additionally, in vivo experiments were conducted to confirm the suppressive impact of CHE on tumor growth in nude mice. The findings revealed that CHE impeded the growth of A2780 and SKOV3 cells in a concentration-time-dependent manner and significantly suppressed the development of tumors in nude mice. CHE elevated the level of oxidative stress in tumor cells, prompted cell cycle halt in the S phase, and increased their mitochondrial membrane potential. Western blotting results demonstrated that CHE could modulate the expression of proteins associated with apoptotic and ferroptosis processes in A2780 and SKOV3 cells. Nrf2 was verified to be an upstream key target mediating the inhibitory impact of CHE on ovarian cancer cells. In summary, CHE exerts its anti-cancer effects on ovarian cancer by modulating Nrf2, inhibiting cellular proliferation, and promoting apoptosis and ferroptosis.

Asunto(s)

Apoptosis , Benzofenantridinas , Proliferación Celular , Ferroptosis , Ratones Desnudos , Factor 2 Relacionado con NF-E2 , Neoplasias Ováricas , Femenino , Benzofenantridinas/farmacología , Humanos , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Neoplasias Ováricas/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/metabolismo , Animales , Línea Celular Tumoral , Ferroptosis/efectos de los fármacos , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Endogámicos BALB C , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo

RESUMEN

The nuclear receptors hepatocyte nuclear factor 4α (HNF4α) and retinoic acid receptor-related orphan receptor-ß (RORß) are ligand-regulated transcription factors and potential drug targets for metabolic disorders. However, there is a lack of small molecular, selective ligands to explore the therapeutic potential in further detail. Here, we report the discovery of greater celandine (Chelidonium majus) isoquinoline alkaloids as nuclear receptor modulators: Berberine is a selective RORß inverse agonist and modulated target genes involved in the circadian clock, photoreceptor cell development, and neuronal function. The structurally related chelidonine was identified as a ligand for the constitutively active HNF4α receptor, with nanomolar potency in a cellular reporter gene assay. In human liver cancer cells naturally expressing high levels of HNF4α, chelidonine acted as an inverse agonist and downregulated genes associated with gluconeogenesis and drug metabolism. Both berberine and chelidonine are promising tool compounds to further investigate their target nuclear receptors and for drug discovery.

Asunto(s)

Berberina , Chelidonium , Factor Nuclear 4 del Hepatocito , Isoquinolinas , Humanos , Berberina/farmacología , Berberina/química , Berberina/síntesis química , Ligandos , Factor Nuclear 4 del Hepatocito/metabolismo , Factor Nuclear 4 del Hepatocito/genética , Chelidonium/química , Isoquinolinas/farmacología , Isoquinolinas/química , Isoquinolinas/síntesis química , Benzofenantridinas/farmacología , Benzofenantridinas/química , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Relación Estructura-Actividad , Células Hep G2 , Relación Dosis-Respuesta a Droga , Estructura Molecular , Línea Celular Tumoral , Chelidonium majus

RESUMEN

Sanguinarine is a quaternary ammonium benzophenanthine alkaloid found in traditional herbs such as Chelidonium, Corydalis, Sanguinarum, and Borovula. It has been proven to possess broad-spectrum biological activities, such as antitumor, anti-inflammatory, antiosteoporosis, neuroprotective, and antipathogenic microorganism activities. In this paper, recent progress on the biological activity and mechanism of action of sanguinarine and its derivatives over the past ten years is reviewed. The results showed that the biological activities of hematarginine and its derivatives are related mainly to the JAK/STAT, PI3K/Akt/mTOR, NF-κB, TGF-ß, MAPK and Wnt/ß-catenin signaling pathways. The limitations of using sanguinarine in clinical application are also discussed, and the research prospects of this subject are outlined. In general, sanguinarine, a natural medicine, has many pharmacological effects, but its toxicity and safety in clinical application still need to be further studied. This review provides useful information for the development of sanguinarine-based bioactive agents.

Asunto(s)

Alcaloides , Fosfatidilinositol 3-Quinasas , Fosfatidilinositol 3-Quinasas/metabolismo , Benzofenantridinas/farmacología , Alcaloides/metabolismo , Isoquinolinas/farmacología

RESUMEN

BACKGROUND: Lung cancer (LC) incidence is rising globally and is reflected as a leading cause of cancer-associated deaths. Lung cancer leads to multistage carcinogenesis with gradually increasing genetic and epigenetic changes. AIMS: Sanguinarine (sang) mediated the anticancer effect in LCC lines by involving the stimulation of reactive oxygen species (ROS), impeding Bcl2, and enhancing Bax and other apoptosis-associated protein Caspase-3, -9, and -PARP, subsequently inhibiting the LC invasion and migration. OBJECTIVE: This study was conducted to investigate the apoptotic rate and mechanism of Sang in human LC cells (LCC) H522 and H1299. METHODS: MTT assay to determine the IC50, cell morphology, and colony formation assay were carried out to show the sanguinarine effect on the LC cell line. Moreover, scratch assay and transwell assay were performed to check the migration. Western blotting and qPCR were done to show its effects on targeted proteins and genes. ELISA was performed to show the VEGF effect after Sanguinarine treatment. Immunofluorescence was done to check the interlocution of the targeted protein. RESULTS: Sang significantly inhibited the growth of LCC lines in both time- and dose-dependent fashions. Flow cytometry examination and Annexin-V labeling determined that Sang increased the apoptotic cell percentage. H522 and H1299 LCC lines treated with Sang showed distinctive characteristics of apoptosis, including morphological changes and DNA fragmentation. CONCLUSION: Sang exhibited anticancer potential in LCC lines and could induce apoptosis and impede the invasion and migration of LCC, emerging as a promising anticancer natural agent in lung cancer management.

Asunto(s)

Antineoplásicos , Isoquinolinas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Apoptosis , Benzofenantridinas/farmacología , Benzofenantridinas/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Estrés Oxidativo

RESUMEN

The objective of the study was to evaluate the in vitro and in vivo schistosomicidal activity of sanguinarine (SA) on Schistosoma mansoni and its in silico pharmacokinetic parameters. ADMET parameters and oral bioavailability were evaluated using the PkCSM and SwissADME platforms, respectively. The activity of SA in vitro, at the concentrations of 1.0-25 µM, was analyzed through the parameters of motility, mortality, and cell viability of the worms at intervals of 3-24 h. Mice were infected with cercariae and treated by gavage with SA (5 mg/kg/day, in a single dose or two doses of 2.5 mg/kg every 12 h for 5 consecutive days) on the 1st (skin schistosomula), 14th (pulmonary schistosomula), 28th (young worms), and 45th (adult worms) days after infection. In vitro and in vivo praziquantel was the control. In vitro, SA showed schistosomicidal activity against schistosomula, young worms, and couples; with total mortality and reduced cell viability at low concentrations and incubation time. In a single dose of 5 mg/kg/day, SA reduces the total worm load by 47.6%, 54%, 55.2%, and 27.1%, and female worms at 52.0%, 39.1%, 52.7%, and 20.2%, respectively, results which are similar to the 2.5 mg/kg/day dose. SA reduced the load of eggs in the liver, and in histopathological and histomorphometric analyses, there was a reduction in the number and volume of hepatic granulomas, which exhibited less inflammatory infiltrate. SA has promising in vitro and in vivo schistosomicidal activity against different developmental stages of S. mansoni, in addition to reducing granulomatous liver lesions. Furthermore, in silico, SA showed good predictive pharmacokinetic ADMET profiles.

Asunto(s)

Alcaloides , Antiinfecciosos , Isoquinolinas , Esquistosomicidas , Femenino , Animales , Ratones , Antiparasitarios , Schistosoma mansoni , Benzofenantridinas/farmacología , Alcaloides/farmacología

RESUMEN

BACKGROUND: The benzophenanthridine Sanguinarine (Sng) is one of the most abundant root alkaloids with a long history of investigation and pharmaceutical applications. The cytotoxicity of Sng against various tumor cells is well-established; however, its antiproliferative and apoptotic potential against the cutaneous squamous cell carcinoma (cSCC) cells remains unknown. In the present study, we investigated the anti-cancer potential of Sng against cSCC cells and elucidated the underlying mechanisms relevant to the drug action. METHODS: The inhibitory effect of Sng on cSCC cells was evaluated by analyzing cell viability, colony-forming ability and multi-caspase activity. Apoptosis was quantified through Annexin-V/Propidium iodide flow cytometric assay and antagonized by pan-caspase inhibitor z-VAD-FMK. Mitochondrial membrane potential (ΔΨm) dysfunction was analyzed by JC-1 staining, whereas reactive oxygen species (ROS) generation was confirmed by pretreatment with N-acetylcysteine (NAC) and fluorogenic probe-based flow cytometric detection. The expression of cell cycle regulatory proteins, apoptotic proteins and MAPK signaling molecules was determined by Western blotting. Involvement of JNK, p38-MAPK and MEK/ERK in ROS-mediated apoptosis was investigated by pretreatment with SP600125 (JNK inhibitor), SB203580 (p38 inhibitor) and U0126 (ERK1/2 inhibitor), respectively. The stemness-targeting potential of Sng was assessed in tumor cell-derived spheroids. RESULTS: Treatment with Sng decreased cell viability and colony formation in primary (A431) and metastatic (A388) cSCC cells in a time- and dose-dependent manner. Sng significantly inhibited cell proliferation by inducing sub-G0/G1 cell-cycle arrest and apoptosis in cSCC cells. Sng evoked ROS generation, intracellular glutathione (GSH) depletion, ΔΨm depolarization and the activation of JNK pathway as well as that of caspase-3, -8, -9, and PARP. Antioxidant NAC inhibited ROS production, replenished GSH levels, and abolished apoptosis induced by Sng by downregulating JNK. Pretreatment with z-VAD-FMK inhibited Sng-mediated apoptosis. The pharmacological inhibition of JNK by SP600125 mitigated Sng-induced apoptosis in metastatic cSCC cells. Finally, Sng ablated the stemness of metastatic cSCC cell-derived spheroids. CONCLUSION: Our results indicate that Sng exerts a potent cytotoxic effect against cSCC cells that is underscored by a mechanism involving multiple levels of cooperation, including cell-cycle sub-G0/G1 arrest and apoptosis induction through ROS-dependent activation of the JNK signaling pathway. This study provides insight into the potential therapeutic application of Sng targeting cSCC.

Asunto(s)

Antracenos , Carcinoma de Células Escamosas , Isoquinolinas , Neoplasias Cutáneas , Humanos , Especies Reactivas de Oxígeno/metabolismo , Benzofenantridinas/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Transducción de Señal , Apoptosis , Sistema de Señalización de MAP Quinasas , Línea Celular Tumoral

RESUMEN

Zika virus (ZIKV) is a mosquito-borne virus that has re-emerged as a significant threat to global health in the recent decade. Whilst infections are primarily asymptomatic, the virus has been associated with the manifestation of severe neurological complications. At present, there is still a lack of approved antivirals for ZIKV infections. In this study, chelerythrine chloride, a benzophenanthridine alkaloid, was identified from a mid-throughput screen conducted on a 502-compound natural products library to be a novel and potent inhibitor of ZIKV infection in both in-vitro and in-vivo assays. Subsequent downstream studies demonstrated that the compound inhibits a post-entry step of the viral replication cycle and is capable of disrupting viral RNA synthesis and protein expression. The successful generation and sequencing of a ZIKV resistant mutant revealed that a single S61T mutation on the viral NS4B allowed ZIKV to overcome chelerythrine chloride inhibition. Further investigation revealed that chelerythrine chloride could directly inhibit ZIKV protein synthesis, and that the NS4B-S61T mutation confers resistance to this inhibition. This study has established chelerythrine chloride as a potential candidate for further development as a therapeutic agent against ZIKV infection.

Asunto(s)

Infección por el Virus Zika , Virus Zika , Animales , Chlorocebus aethiops , Infección por el Virus Zika/tratamiento farmacológico , Benzofenantridinas/farmacología , Benzofenantridinas/metabolismo , Benzofenantridinas/uso terapéutico , Células Vero , Proteínas Virales/metabolismo , Replicación Viral , Antivirales/uso terapéutico

RESUMEN

Defects in cell death signaling pathways are one of the hallmarks of cancer and can lead to resistance to conventional therapy. Natural products are promising compounds that can overcome this resistance. In the present study we studied the effect of six quaternary benzophenanthridine alkaloids (QBAs), sanguinarine, chelerythrine, sanguirubine, chelirubine, sanguilutine, and chelilutine, on Jurkat leukemia cells, WT, and cell death deficient lines derived from them, CASP3/7/6-/- and FADD-/-, and on solid tumor, human malignant melanoma, A375 cells. We demonstrated the ability of QBAs to overcome the resistance of these deficient cells and identified a novel mechanism for their action. Sanguinarine and sanguirubine completely and chelerythrine, sanguilutine, and chelilutine partially overcame the resistance of CASP3/7/6-/- and FADD-/- cells. By detection of cPARP, a marker of apoptosis, and pMLKL, a marker of necroptosis, we proved the ability of QBAs to induce both these cell deaths (bimodal cell death) with apoptosis preceding necroptosis. We identified the new mechanism of the cell death induction by QBAs, the downregulation of the apoptosis inhibitors cIAP1 and cIAP2, i.e., an effect similar to that of Smac mimetics.

Asunto(s)

Alcaloides , Apoptosis , Humanos , Benzofenantridinas/farmacología , Caspasa 3/metabolismo , Alcaloides/farmacología , Alcaloides/metabolismo , Transducción de Señal , Línea Celular Tumoral