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An increased risk of developing severe dengue has been linked to the VEGF gene. Angiogenesis, which is involved in developing and maintaining blood vessels, is controlled by the VEGF protein. In addition to influencing immunological responses, VEGF is a major contributing factor in the increased vascular permeability seen in severe dengue patients. Technology and transportation advancements have made it possible for dengue to travel quickly, and outbreaks of the disease are now occurring in several nations across several continents, putting billions of people's life in danger. This research aimed to perform mutational analysis of VEGF in dengue serotypes 1 and 2 patients and find potential antiviral inhibitors for dengue treatment. 144 samples were analyzed, 72 cases and 72 controls. Mutational analysis was done by performing tetra arms PCR. Results showed no significant difference in allele frequency among patients and controls. 89% of samples and 96% of controls had Allele C. In comparison, 6% of samples and 3% of controls had Allele A (p<0.0001) showing heterozygous condition. Bioinformatic analysis was done to find potential antiviral phytochemicals that would be effective for the treatment of dengue. Upon bioinformatic analysis, artemisinin, sanguinarine, chelidonine, glycyrrhisoflavone, and taspine showed strong binding energies of -8.7 to -7.8 to NS-1viral protein. In conclusion, no genetic association existed between SNP and phenotypic traits of dengue. The extensive transmission and serious effects of dengue make it a serious worldwide health issue. To create efficient treatments and preventive measures to combat dengue, it is essential to understand the genetic and molecular features of the virus and host response. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is currently the most frequent and lethal cancer among women, and therefore, identification of novel biomarkers and potential anticancer agents for BC is crucial. Chelidonine is one of the main active ingredients of Chelidonium majus, which has been applied in Chinese medicine prescriptions to treat cancer. This paper aimed to evaluate the ability of chelidonine to trigger mitotic catastrophe in BC cells and to clarify its mechanism through the AKT/FOXO3/FOXM1 pathway. Bioinformatics analysis revealed that forkhead box O3 (FOXO3) was downregulated in different subtypes of BC. Factors such as age, stage, Scarff-Bloom-Richardson (SBR) grade, diverse BC subclasses, and triple-negative status were inversely correlated to FOXO3 levels in BC patients compared with healthy controls. Notably, patients exhibiting higher FOXO3 expression levels demonstrated better overall survival (OS) and relapse-free survival (RFS). Moreover, FOXM1 levels were negatively correlated with both OS and RFS in BC patients. These results revealed that FOXO3 might be considered a predictive biomarker for the prognosis of BC. By utilizing Gene Set Enrichment Analysis (GSEA), we delved into the main Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathways of FOXO3, and the results suggested that FOXO3 was mainly involved in cancer-related pathways and the cell cycle. Thereafter, MTT and flow cytometry (FCM) analysis indicated that chelidonine inhibited BC cell line proliferation and induced M phase arrest. It was found that chelidonine treatment induced MCF-7 cell apoptosis, significantly reduced the expression of survivin and promoted the expression of p53 and caspase-9. Further morphological observation illustrated depolymerization of the actin skeleton and shortening of actin filaments in BC cells, leading to the typical characteristics of mitotic catastrophe, such as abnormal mitosis and multinucleated cells. Western blot analysis demonstrated that chelidonine inhibited the expression of p-AKT to promote the expression of FOXO3 protein and weaken the expression levels of FOXM1 and polo-like kinase 1 (PLK1). Taken together, our present work proved that FOXO3 might be considered a potential therapeutic target for BC. Chelidonine emerges as a promising agent to treat BC by inducing M phase arrest of BC cells and hindering the AKT/FOXO3/FOXM1 axis, thereby inducing mitotic catastrophe in BC.

Chondrocyte inflammation and catabolism are two major features in the progression of osteoarthritis (OA). Chelidonine, a principal alkaloid extracted from Chelidonium majus, is suggested to show anti-inflammation, anti-apoptosis, and anti-oxidation activities in various diseases. However, its potential effects on OA cartilage degeneration remains unclear. To evaluate the effect of chelidonine on OA and its underlying mechanism, we incubated chondrocytes with interleukin (IL)-1β and chelidonine at varying concentrations. Then, we performed the CCK-8 assay, fluorescence immunostaining, reverse transcription PCR, ELISA, and western blotting to evaluate cell viability, catabolic/inflammatory factors, levels of extracellular matrix (ECM)-related proteins, and the involved pathways. H&E and Safranin-O staining and ELISA were performed to measure cartilage degradation and synovial inflammation. Chelidonine suppressed the IL-1β-mediated catabolism and inflammation of chondrocytes. Chelidonine suppressed the NF-κB pathway activation. Similarly, our in vivo experiment showed that chelidonine partially attenuated cartilage degradation while inhibiting synovial inflammation. Chelidonine inhibited inflammation and catabolism through modulation of NF-κB pathways in vitro, thereby avoiding rat cartilage degeneration and synovial inflammation within OA.

Background. In recent years, many drugs approved by Food and Drug Administration have been withdrawn from the pharmaceutical industry due to their off-target effects, which often lead to cardio cytotoxicity. As a result, there is an increasing interest in the identification of drugs with potential impact on the cardiac rhythm at early stages of the drug development process, as well as the way to reduce their cardiotoxic effects. Nowadays, several cell-based assays identify inhibitors and modulators of cardiac functions. FluxOR assay is one of the important cell models for investigating cardio cytotoxicity in vitro. It is based on the usage of HEK293-hERG cell line expressing the hERG (Human Ether-à-go-go Related Gene) potassium channel, which has a key role in regulation of the heart rhythm. Chelidonin is a secondary metabolite of Chelidonium majus L. It was shown that Chelidonin inhibits cell proliferation and induces mitotic arrest, which in turn is accompanied by an increase in the number of cells with apoptosis. Currently, Chelidonin is considered a potential anti-tumor drug, so the investigation of its potential offtarget effects and the way to reduce them is important. Due to the antioxidant properties of fullerene C60 and its ability to protect cells from oxidative stress, it is a promising candidate for reducing the cardiotoxic effects of certain drugs. Aim. Our study aimed at investigating the effect of plant alkaloid Chelidonin as a monotherapy and in the co-treatment with carbon nanoparticles fullerene C60 on the K+ ion permeability through hERG potassium channel using FluxOR assay. Methods. The stably transfected HEK293-hERG cells were treated with Chelidonin alone, C60 fullerene alone, or with a mixture of Chelidonin and C60 fullerene. The activity of the hERG channels was measured using FluxOR assay kit. Real-time changes in the activity of potassium channels were measured using FLIPR Tetra High Throughput Screening System. The data were analyzed with ScreenWorks v.3.2 software. Results. Dose-dependent inhibition of K+ channels permeability in the HEK293-hERG cells was found after 30-min treatment with Chelidonin in the concentration range of 0.1– 200 μM. The IC50 value in HEK293-hERG cells for alkaloid was 24.9 μM. C60 fullerene in the concentration range of 0.02–40 μM did not affect the inhibition of potassium channels. The IC50 value under the combined action of Chelidonin and C60 fullerene was increased by 3.9-fold compared to the IC50 value for Chelidonin alone and amounted to 97.8 μM. The obtained results indicated a positive effect of C60 fullerene nanoparticles, as evidenced by an increase in K+ permeability through ion channels under the action of the alkaloid. Conclusions. Thus, studies on potassium channels permeability are extremely important due to their wide-ranging effects on various physiological processes. The use of the FluxOR screening assay is an effective tool for identifying molecules that inhibit the cellular hERG potassium channels. The inhibitory effect of Chelidonin on the hERG potassium channels can be reduced by C60 fullerene nanoparticles. [ABSTRACT FROM AUTHOR]

The Chelidonium majus plant is rich in biologically active isoquinoline alkaloids. These alkaline polar compounds are isolated from raw materials with the use of acidified water or methanol; next, after alkalisation of the extract, they are extracted using chloroform or dichloromethane. This procedure requires the use of toxic solvents. The present study assessed the possibility of using volatile natural deep eutectic solvents (VNADESs) for the efficient and environmentally friendly extraction of Chelidonium alkaloids. The roots and herb of the plant were subjected three times to extraction with various menthol, thymol, and camphor mixtures and with water and methanol (acidified and nonacidified). It has been shown that alkaloids can be efficiently isolated using menthol–camphor and menthol–thymol mixtures. In comparison with the extraction with acidified methanol, the use of appropriate VNADESs formulations yielded higher amounts of protopine (by 16%), chelidonine (35%), berberine (76%), chelerythrine (12%), and coptisine (180%). Sanguinarine extraction efficiency was at the same level. Additionally, the values of the contact angles of the raw materials treated with the tested solvents were assessed, and higher wetting dynamics were observed in the case of VNADESs when compared with water. These results suggest that VNADESs can be used for the efficient and environmentally friendly extraction of Chelidonium alkaloids. [ABSTRACT FROM AUTHOR]

Natural compounds represent the great capability to stimulate several cell types. Macrophage plays an important role for an effective immune response for infection and inflammation. Isoquinoline alkaloid, sanguinarine, and chelidonine are active compounds that exhibit activity on various tumor cells and immune cells. However, the effect of these compounds on the endosomal toll-like receptor (enTLR) and type I interferon (IFN) are still unclear. The monocyte-derived macrophages (MDMs) were cultured and were determined their cell viability and phagocytic activity to Staphylococcus aureus DMST8840. The nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression were also examined. The expression of enTLRs, type I IFN, and cytokines were determined by real-time PCR. Result shows that the compounds did not affect on MDM cell viability. Sanguinarine and chelidonine enhance phagocytic activity of MDM against Staphylococcus aureus DMST8840 by revealing a higher number of bacterial survival than the MDM treated by polyI:C, and the cell control after co-culture for 3 h. The production of NO has no difference amount but iNOS mRNA production was down-regulated in sanguinarine, chelidonine and their mixed treated MDM. The expressions of enTLRs and IFN-β1 mRNA were up-regulated in both compounds and their combination. Additionally, these compounds also enhance M1-liked cytokine by up-regulated IL-6 and down-regulated IL-10 and TGF-β1, respectively. Therefore, sanguinarine and chelidonine enhance enTLR and IFN-β1 expression and trend to stimulate the cell into M1-liked MDM.

This study aims to explore the pharmacodynamics of chelidonine, the active ingredient in greater celandine (Chelidonium majus L.), on in vitro rat bladder and trachea tissue, and evaluate its cell protective effects on primary lung and kidney cell lines. The study was carried out via repeated applications of acetylcholine, atropine, verapamil and oxybutynin, alongside Ca++ in a calcium-free environment, on urinary bladder tissue, and repeated applications of acetylcholine, atropine, carbachol and mecamylamine on trachea tissue. At the same time, cell viability and catalase and superoxide dismutase activity was measured on primary cell lines obtained from lung and kidney tissue samples. The study has shown that chelidonine has a relaxant effect on bladder and trachea tissues, and it may be mentioned that this effect is produced via muscarinic receptors. In addition, chelidonin caused a statistically insignificant increase in cell viability in primary lung and kidney cell lines at increasing doses (1 and 4 μg/ mL), but this increase remained at the control group level. In contrast, chelidonin caused a significant decrease in cell viability at the same cell lines at doses of 8 and 16 μg/mL. In conclusion, it is suggested that greater celandine, which is used in folk medicine, and its active ingredient chelidonine might have beneficial effects on asthma, urinary incontinence and other urinary tract and respiratory diseases among others.

The Chelidonium majus plant is rich in biologically active isoquinoline alkaloids. These alkaline polar compounds are isolated from raw materials with the use of acidified water or methanol; next, after alkalisation of the extract, they are extracted using chloroform or dichloromethane. This procedure requires the use of toxic solvents. The present study assessed the possibility of using volatile natural deep eutectic solvents (VNADESs) for the efficient and environmentally friendly extraction of Chelidonium alkaloids. The roots and herb of the plant were subjected three times to extraction with various menthol, thymol, and camphor mixtures and with water and methanol (acidified and nonacidified). It has been shown that alkaloids can be efficiently isolated using menthol–camphor and menthol–thymol mixtures. In comparison with the extraction with acidified methanol, the use of appropriate VNADESs formulations yielded higher amounts of protopine (by 16%), chelidonine (35%), berberine (76%), chelerythrine (12%), and coptisine (180%). Sanguinarine extraction efficiency was at the same level. Additionally, the values of the contact angles of the raw materials treated with the tested solvents were assessed, and higher wetting dynamics were observed in the case of VNADESs when compared with water. These results suggest that VNADESs can be used for the efficient and environmentally friendly extraction of Chelidonium alkaloids.

We have examined the mechanism underlying amelioration of sepsis-induced acute lung injury by chelidonine in newborn mice. To this end, a sepsis model was established using cecal ligation and puncture in newborn mice. The sepsis-induced acute lung injury was associated with an increased inflammatory infiltration and pulmonary congestion, as well as abnormal alveolar morphology. The lung injury-associated increased tumor necrosis factor-a and interleukin-1ß in bronchoalveolar lavage fluid and lung, the markers of inflammatory infiltration and pulmonary congestion, diminished by chelidonine treatment. Chelidonine administration also downregulated protein levels of toll-like receptor 4, myeloid differentiation factor 88, phosphorylatedWe have examined the mechanism underlying amelioration of sepsis-induced acute lung injury by chelidonine in newborn mice. To this end, a sepsis model was established using cecal ligation and puncture in newborn mice. The sepsis-induced acute lung injury was associated with an increased inflammatory infiltration and pulmonary congestion, as well as abnormal alveolar morphology. The lung injury-associated increased tumor necrosis factor-a and interleukin-1ß in bronchoalveolar lavage fluid and lung, the markers of inflammatory infiltration and pulmonary congestion, diminished by chelidonine treatment. Chelidonine administration also downregulated protein levels of toll-like receptor 4, myeloid differentiation factor 88, phosphorylated nuclear factor-kappa B, and nuclear factor-kappa B that are elevated in response to sepsis. In conclusion, chelidonine provides a potential therapeutic strategy for newborn mice with acute lung injury. nuclear factor-kappa B, and nuclear factor-kappa B that are elevated in response to sepsis. In conclusion, chelidonine provides a potential therapeutic strategy for newborn mice with acute lung injury. [ABSTRACT FROM AUTHOR]

Chelidonium majus has been used as a traditional medicine in China and western countries for various diseases, including inflammation and cancer. However, the anti-cancer effect of chelidonine, a major compound of C. majus extracts, on pancreatic cancer remains poorly understood. In this study, we found that treatment with chelidonine inhibited proliferation of BxPC-3 and MIA PaCa-2 human pancreatic cancer cells. Annexin-V/propidium iodide staining assay showed that this growth inhibitory effect of chelidonine was induced through apoptosis. We found that chelidonine treatment upregulated mRNA levels and transcription factor activity in both cell lines. Increases in protein expression levels of p53, GADD45A, p21 and cleaved caspase-3 were also observed, with more distinct changes in MIA PaCa-2 cells compared to the BxPC-3 cells. These results suggest that chelidonine induces pancreatic cancer apoptosis through the p53 and GADD45A pathways. Our findings provide new insights into the use of chelidonine for the treatment of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Natural compounds represent the great capability to stimulate several cell types. Macrophage plays an important role for an effective immune response for infection and inflammation. Isoquinoline alkaloid, sanguinarine, and chelidonine are active compounds that exhibit activity on various tumor cells and immune cells. However, the effect of these compounds on the endosomal toll-like receptor (enTLR) and type I interferon (IFN) are still unclear. The monocyte-derived macrophages (MDMs) were cultured and were determined their cell viability and phagocytic activity to Staphylococcus aureus DMST8840. The nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression were also examined. The expression of enTLRs, type I IFN, and cytokines were determined by real-time PCR. Result shows that the compounds did not affect on MDM cell viability. Sanguinarine and chelidonine enhance phagocytic activity of MDM against Staphylococcus aureus DMST8840 by revealing a higher number of bacterial survival than the MDM treated by polyI:C, and the cell control after co-culture for 3 h. The production of NO has no difference amount but iNOS mRNA production was down-regulated in sanguinarine, chelidonine and their mixed treated MDM. The expressions of enTLRs and IFN-ß1 mRNA were up-regulated in both compounds and their combination. Additionally, these compounds also enhance M1-liked cytokine by up-regulated IL-6 and down-regulated IL-10 and TGF-ß1, respectively. Therefore, sanguinarine and chelidonine enhance enTLR and IFN-ß1 expression and trend to stimulate the cell into M1-liked MDM. [ABSTRACT FROM AUTHOR]

This study aims to explore the pharmacodynamics of chelidonine, the active ingredient in greater celandine (Chelidonium majus L.), on in vitro rat bladder and trachea tissue, and evaluate its cell protective effects on primary lung and kidney cell lines. The study was carried out via repeated applications of acetylcholine, atropine, verapamil and oxybutynin, alongside Ca++ in a calcium-free environment, on urinary bladder tissue, and repeated applications of acetylcholine, atropine, carbachol and mecamylamine on trachea tissue. At the same time, cell viability and catalase and superoxide dismutase activity was measured on primary cell lines obtained from lung and kidney tissue samples. The study has shown that chelidonine has a relaxant effect on bladder and trachea tissues, and it may be mentioned that this effect is produced via muscarinic receptors. In addition, chelidonin caused a statistically insignificant increase in cell viability in primary lung and kidney cell lines at increasing doses (1 and 4 µg/mL), but this increase remained at the control group level. In contrast, chelidonin caused a significant decrease in cell viability at the same cell lines at doses of 8 and 16 µg/mL. In conclusion, it is suggested that greater celandine, which is used in folk medicine, and its active ingredient chelidonine might have beneficial effects on asthma, urinary incontinence and other urinary tract and respiratory diseases among others. [ABSTRACT FROM AUTHOR]

In the quest for selective G-quadruplex (G4)-targeting chemotypes, natural compounds have been thus far poorly explored, though representing appealing candidates due to the high structural diversity of their scaffolds. In this regard, a unique high diversity in-house library composed of ca. one thousand individual natural products was investigated. The combination of molecular docking-based virtual screening and the G4-CPG experimental screening assay proved to be useful to quickly and effectively identify—out of many natural compounds—five hit binders of telomeric and oncogenic G4s, i.e., Bulbocapnine, Chelidonine, Ibogaine, Rotenone and Vomicine. Biophysical studies unambiguously demonstrated the selective interaction of these compounds with G4s compared to duplex DNA. The rationale behind the G4 selective recognition was suggested by molecular dynamics simulations. Indeed, the selected ligands proved to specifically interact with G4 structures due to peculiar interaction patterns, while they were unable to firmly bind to a DNA duplex. From biological assays, Chelidonine and Rotenone emerged as the most active compounds of the series against cancer cells, also showing good selectivity over normal cells. Notably, the anticancer activity correlated well with the ability of the two compounds to target telomeric G4s.

Chelidonium majus L. is a herbal medicine widely employed in Europe and Western Asia. Chelidonine (CHE) is a major constituent of the herb and has been reported to be an inhibitor of the cytochrome P450 enzymes (CYP). The major objective of the present study was to study the metabolic pathways of CHE in order to identify potential reactive metabolites responsible for the enzyme inhibition. Three oxidative metabolites (M1-M3) were detected in human liver microsomal incubations after exposure to CHE. M1 and M2 were two isomers of catechol derivatives, and M3 was a dicatechol compound. The M1-M3 metabolites were also observed in bile of rats given CHE. A total of five glutathione (GSH) conjugates (M4-M8) were detected in microsomes containing CHE, GSH, and NADPH. Moreover, M4 and M6 originated from M1, M5 and M7 resulted from M2, and M8 was a M3-derived GSH conjugate. Three biliary CHE-derived GSH conjugates (M4, M5 and M8) were found in CHE-treated rats. This indicates that CHE was bioactivated to ortho -quinone derivatives both in vitro and in vivo. Recombinant P450 enzyme incubations demonstrated that the CYPs3A4, 1A2, 2C19 and 2D6 were mainly involved in metabolic activation of CHE. This study generated data that may be useful in understanding possible mechanisms of CHE-induced P450 inhibition. • Quinone derivatives were detected both in vitro and in vivo after exposed to chelidonine. • Quinone intermediates derived from chelidonine were reactive to nucleophilic GSH. • P450 3A4, 1A2, 2C19 and 2D6 were the primary enzymes responsible for the metabolic activation of chelidonine. [ABSTRACT FROM AUTHOR]

As antique as Dioscorides era are the first records on using Chelidonium as a remedy to several sicknesses. Inspired by the “signatura rerum” principle and an apparent ancient folk tradition, various indications were given, such as anti-jaundice and cholagogue, pain-relieving, and quite often mentioned—ophthalmological problems. Central and Eastern European folk medicine has always been using this herb extensively. In this region, the plant is known under many unique vernacular names, especially in Slavonic languages, associated or not with old Greek relation to “chelidon”—the swallow. Typically for Papaveroidae subfamily, yellow-colored latex is produced in abundance and leaks intensely upon injury. Major pharmacologically relevant components, most of which were first isolated over a century ago, are isoquinoline alkaloids—berberine, chelerythrine, chelidonine, coptisine, sanguinarine. Modern pharmacology took interest in this herb but it has not ended up in gaining an officially approved and evidence-based herbal medicine status. On the contrary, the number of relevant studies and publications tended to drop. Recently, some controversial reports and sometimes insufficiently proven studies appeared, suggesting anticancer properties. Anticancer potential was in line with anecdotical knowledge spread in East European countries, however, in the absence of directly-acting cytostatic compounds, some other mechanisms might be involved. Other properties that could boost the interest in this herb are antimicrobial and antiviral activities. Being a common synanthropic weed or ruderal plant, C. majus spreads in all temperate Eurasia and acclimates well to North America. Little is known about the natural variation of bioactive metabolites, including several aforementioned isoquinoline alkaloids. In this review, we put together older and recent literature data on phytochemistry, pharmacology, and clinical studies on C. majus aiming at a critical evaluation of state-of-the-art from the viewpoint of historical and folk indications. The controversies around this herb, the safety and drug quality issues and a prospective role in phytotherapy are discussed as well.

Graphical abstract Highlights • Chelidonine, one of the alkaloids, exerted obvious anti-inflammatory effects under LPS stimulation both in vivo and in vitro. • TLR4/NF-κB signaling pathway played an important role in Chelidonine's pharmacological activity to inhibit inflammation. • Mice may keep away from LPS disturbance when administrated with Chelidonine 12 days in advance, displaying the potential of Chelidonine in preventing inflammation. • The pharmacological activity of Chelidonine may be achieved through multi-signaling regulation, which need more experiment to be elucidate. Abstract Chelidonine is one of the alkaloids of Chelidonium majus, which has broad pharmacological activities, including anti-inflammatory. Despite chelidonine has been shown to exhibit anti-inflammatory activity, the molecular mechanisms are not yet fully elucidated. In this paper, we used RAW264.7 macrophages and mice to investigate the anti-inflammatory effects of chelidonine. Firstly, we found that chelidonine significantly suppressed LPS-induced the production of NO and PGE 2 , as well as iNOS and COX-2 mRNA and protein expression. In addition, pro-inflammatory cytokines induced by LPS, such as TNFα and IL-6 were also attenuated by chelidonine. What's more, LPS-induced activation and degradation of IκBα followed by translocation of the p65 from the cytoplasm to the nucleus were attenuated by chelidonine. Furthermore, chelidonine even significantly inhibited TLR4 expression induced by LPS. Finally, we verified that chelidonine striking ly decreased serum TNFα, IL-6 and PGE 2 levels in LPS stimulated mice. Taken together, this study demonstrated that chelidonine may suppressed the LPS-induced inflammatory response both in vitro and in vivo, which was relating to TLR4/NF-κB signaling pathway disturbed by chelidonine. [ABSTRACT FROM AUTHOR]

The greater celandine ‘Chelidonium majus’ and its main alkaloid chelidonine have previously been shown to exert high cytotoxicity against cancer cells. Furthermore, chelidonine is proposed to possess pro-apoptotic and anti-metastatic properties. Within the present study, the effects chelidonine on several HNSCC cell lines, as well as primary cells, were analyzed with respect to growth, migration, angiogenesis and apoptosis. Chelidonine suppressed the growth of all tested HNSCC cell lines, including a paclitaxel-resistant and P-glycoprotein (MDR1) overexpressing cell line, but not in a clear dose-dependent manner. Mucosal keratinocytes were also strongly affected by chelidonine, while fibroblasts proved to be much more resistant. Chelidonine failed to trigger apoptosis at physiological concentrations in HNSCC cell lines. Based on a spheroid invasion model chelidonine suppressed invasion of FaDu cells effectively on gelatin, fibronectin, collagen I, laminin and Matrigel®. However, invasion inhibition of the more aggressively invading cell line HLaC78 largely failed. Using the tube formation assay, chelidonine effectively inhibited angiogenesis. Expression analysis revealed an upregulation of the xenobiotic metabolism genes CYP1A1 and MDR1 by chelidonine. In summary, chelidonine appeared to exert only minor impact on head and neck cancer cells. Chelidonine did not produce clear dose-dependent and cell-type specific cytotoxicity nor did it trigger apoptosis strongly. [ABSTRACT FROM AUTHOR]

As antique as Dioscorides era are the first records on using Chelidonium as a remedy to several sicknesses. Inspired by the "signatura rerum" principle and an apparent ancient folk tradition, various indications were given, such as anti-jaundice and cholagogue, pain-relieving, and quite often mentioned--ophthalmological problems. Central and Eastern European folk medicine has always been using this herb extensively. In this region, the plant is known under many unique vernacular names, especially in Slavonic languages, associated or not with old Greek relation to "chelidon"-- the swallow. Typically for Papaveroidae subfamily, yellow-colored latex is produced in abundance and leaks intensely upon injury. Major pharmacologically relevant components, most of which were first isolated over a century ago, are isoquinoline alkaloids-- berberine, chelerythrine, chelidonine, coptisine, sanguinarine. Modern pharmacology took interest in this herb but it has not ended up in gaining an officially approved and evidence-based herbal medicine status. On the contrary, the number of relevant studies and publications tended to drop. Recently, some controversial reports and sometimes insufficiently proven studies appeared, suggesting anticancer properties. Anticancer potential was in line with anecdotical knowledge spread in East European countries, however, in the absence of directly-acting cytostatic compounds, some other mechanisms might be involved. Other properties that could boost the interest in this herb are antimicrobial and antiviral activities. Being a common synanthropic weed or ruderal plant, C. majus spreads in all temperate Eurasia and acclimates well to North America. Little is known about the natural variation of bioactive metabolites, including several aforementioned isoquinoline alkaloids. In this review, we put together older and recent literature data on phytochemistry, pharmacology, and clinical studies on C. majus aiming at a critical evaluation of state-of-the-art from the viewpoint of historical and folk indications. The controversies around this herb, the safety and drug quality issues and a prospective role in phytotherapy are discussed as well. [ABSTRACT FROM AUTHOR]

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a complex that regulates several hundreds of genes, including those involved in immunity and inflammation, survival, proliferation, and the negative feedback of NF-κB signaling. Chelidonine, a major bioactive, isoquinoline alkaloid ingredient in Chelidonium majus, exhibits antiinflammatory pharmacological properties. However, its antiinflammatory molecular mechanisms remain unclear. In this work, we explored the effect of chelidonine on TNF-induced NF-κB activation in HCT116 cells. We found chelidonine inhibited the phosphorylation and degradation of the inhibitor of NF-κB alpha and nuclear translocation of RELA. Furthermore, by inhibiting the activation of NF-κB, chelidonine downregulated target genes involved in inflammation, proliferation, and apoptosis. Chelidonine also inhibited mitogen-activated protein kinase pathway activation by blocking c-Jun N-terminal kinase and p38 phosphorylation. These results suggest that chelidonine may be a potential therapeutic agent against inflammatory diseases in which inhibition of NF-κB activity plays an important role. [ABSTRACT FROM AUTHOR]

Chelidonium majus L. (greater celandine) has been used as an herbal medicine for several centuries. This study investigated an efficient method to purify chelidonine from the extract of C. majus L. using macroporous adsorption resins and evaluated the antifungal activity of chelidonine against Botryosphaeria dothidea as a model strain. Static adsorption and desorption tests revealed that D101 was the optimal resin for chelidonine purification. Pseudo-second-order kinetics model and Freundlich equation model were the most suitable for evaluating the endothermic and spontaneous adsorption processes of chelidonine on D101. Dynamic adsorption and desorption tests on D101 columns showed that the concentration of chelidonine increased 14.16-fold, from 2.67% to 37.81%, with the recovery yield of 80.77%. The antifungal activity of enriched chelidonine products was studied with B. dothidea . The results showed that the EC 50 of crude extracts, enriched chelidonine products, and chelidonine standard against B. dothidea were 3.24 mg/mL, 0.43 mg/mL, and 0.77 mg/mL, respectively. The result of antifungal activity test showed that chelidonine had the potential to be a useful antifungal agent. Moreover, the enrichment method of chelidonine was highly efficient, low cost, and harmless to the environment for industrial applications. [ABSTRACT FROM AUTHOR]

Background Natural bioproducts are invaluable resources in drug discovery. Isoquinoline alkaloids of Chelidonium majus constitute a structurally diverse family of natural products that are of great interest, one of them being their selectivity for human telomeric G-quadruplex structure and telomerase inhibition. Methods The study focuses on the mechanism of telomerase inhibition by stabilization of telomeric G-quadruplex structures by berberine, chelerythrine, chelidonine, sanguinarine and papaverine. Telomerase activity and mRNA levels of hTERT were estimated using quantitative telomere repeat amplification protocol ( q- TRAP) and qPCR, in MCF-7 cells treated with different groups of alkaloids. The selectivity of the main isoquinoline alkaloids of Chelidonium majus towards telomeric G-quadruplex forming sequences were explored using a sensitive modified thermal FRET-melting measurement in the presence of the complementary oligonucleotide CT22. We assessed and monitored G-quadruplex topologies using circular dichroism (CD) methods, and compared spectra to previously well-characterized motifs, either alone or in the presence of the alkaloids. Molecular modeling was performed to rationalize ligand binding to the G-quadruplex structure. Results The results highlight strong inhibitory effects of chelerythrine, sanguinarine and berberine on telomerase activity, most likely through substrate sequestration. These isoquinoline alkaloids interacted strongly with telomeric sequence G-quadruplex. In comparison, chelidonine and papaverine had no significant interaction with the telomeric quadruplex, while they strongly inhibited telomerase at transcription level of hTERT. Altogether, all of the studied alkaloids showed various levels and mechanisms of telomerase inhibition. Conclusions We report on a comparative study of anti-telomerase activity of the isoquinoline alkaloids of Chelidonium majus . Chelerythrine was most effective in inhibiting telomerase activity by substrate sequesteration through G-quadruplex stabilization. General significance Understanding structural and molecular mechanisms of anti-cancer agents can help in developing new and more potent drugs with fewer side effects. Isoquinolines are the most biologically active agents from Chelidonium majus , which have shown to be telomeric G-quadruplex stabilizers and potent telomerase inhibitors. [ABSTRACT FROM AUTHOR]

Alkaloids, the largest group among the nitrogen-containing secondary metabolites of plants, usually interact with several molecular targets. In this study, we provide evidence that six cytotoxic alkaloids (sanguinarine, chelerythrine, chelidonine, noscapine, protopine, homoharringtonine), which are known to affect neuroreceptors, protein biosynthesis and nucleic acids, also interact with the cellular cytoskeleton, such as microtubules and actin filaments, as well. Sanguinarine, chelerythrine and chelidonine depolymerized the microtubule network in living cancer cells (Hela cells and human osteosarcoma U2OS cells) and inhibited tubulin polymerization in vitro with IC50 values of 48.41 ± 3.73, 206.39 ± 4.20 and 34.51 ± 9.47 μM, respectively. However, sanguinarine and chelerythrine did not arrest the cell cycle while 2.5 μM chelidonine arrested the cell cycle in the G2/M phase with 88.27% ± 0.99% of the cells in this phase. Noscapine and protopine apparently affected microtubule structures in living cells without affecting tubulin polymerization in vitro, which led to cell cycle arrest in the G2/M phase, promoting this cell population to 73.42% ± 8.31% and 54.35% ± 11.26% at a concentration of 80 μM and 250.9 μM, respectively. Homoharringtonine did not show any effects on microtubules and cell cycle, while the known microtubule-stabilizing agent paclitaxel was found to inhibit tubulin polymerization in the presence of MAPs in vitro with an IC50 value of 38.19 ± 3.33 μM. Concerning actin filaments, sanguinarine, chelerythrine and chelidonine exhibited a certain effect on the cellular actin filament network by reducing the mass of actin filaments. The interactions of these cytotoxic alkaloids with microtubules and actin filaments present new insights into their molecular modes of action. [ABSTRACT FROM AUTHOR]

Background: Chelidonine is a potent anticancer against several cell lines. However, low bioavailability and water solubility restrict the clinical applications of this compound., Objective: The aim of this research was to develop a novel formulation of chelidonine encapsulated in the nanoparticles of poly(d l-lactic-co-glycolic acid) (PLGA) employing vitamin E D-α-tocopherol acid polyethylene glycol 1000 succinate (E TPGS) as a modifier to increase bioavailability., Methods: Chelidonine-encapsulated PLGA nanoparticles were fabricated using a single emulsion method and modified by various concentrations of E TPGS. Nanoparticles were recognized in terms of morphology, surface charge, drug release, size, drug loading, and encapsulation efficiency to obtain the optimized formulation. The cytotoxicity of different nanoformulations in HT-29 cells was evaluated using the MTT assay. The cells were stained with propidium iodide and annexin V solution to evaluate apoptosis using flow cytometry., Results: Spherical nanoparticles prepared with 2% (w/v) of E TPGS had the optimum formulation in the nanometer size range (153 ± 12.3 nm), with a surface charge of -14.06 ± 2.21 mV, encapsulation efficiency of 95.58 ± 3.47%, drug loading of 33.13 ± 0.19%, and drug release profile of 73.54 ± 2.33. In comparison with non-modified nanoparticles and free chelidonine, E TPGS-modified nanoformulations improved anti-cancer capability even after three-months storage., Conclusion: Our results showed that E TPGS is an effective biomaterial for surface modification of nanoparticles, which can serve as a potential treatment for cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Metastasis is the primary cause of cancer-associated mortality. The ternary IPP complex of integrin-linked kinase, PINCH and parvin functions as a signaling platform for integrins, which modulate numerous cellular processes including cell migration and invasion. Chelidonine, isolated from Chelidonium majus, is a benzophenanthridine alkaloid that exhibits anticancer properties; however, the anti-migratory and anti-invasive effects of chelidonine remain unknown. The aim of the present study was to investigate the inhibitory effects of chelidonine on migration and invasion of MDA-MB-231 human breast cancer cells, and to determine the underlying mechanisms. Chelidonine was shown to inhibit the migration and invasion of MDA-MB-231 cells in a concentration-dependent manner, without affecting the cell viability. Chelidonine did not significantly inhibit the adhesion of the cells to type 1 collagen (COL-I), however it did affect cell spreading and reorganization of the actin cytoskeleton. Chelidonine also inhibited COL-I-induced protein kinase B (Akt) activation and translocation to the plasma membrane, however, it did not significantly inhibit the activation of focal adhesion kinase. Notably, chelidonine treatment significantly inhibited COL-I-induced formation of the IPP complex and activation of IPP downstream signaling molecules, such as extracellular signal-regulated kinase (ERK)1/2. These results suggest that chelidonine exhibits anti-migratory and anti-invasive effects in MDA-MB-231 cells, by suppressing COL-I-induced integrin signaling, through inhibiting the formation of the IPP complex and subsequent down-regulation of IPP downstream signaling molecules, such as Akt and ERK1/2. These results suggest that chelidonine may be a potential therapeutic agent against metastasis of invasive human cancer cells. [ABSTRACT FROM AUTHOR]

In a preliminary study screening anti-proliferative natural alkaloids, a very potent benzophenanthridine, chelidonine showed strong cytotoxicity in cancer cells. While several modes of death have been identified, most of anti-cancer attempts have focused on stimulation of cells to undergo apoptosis. Chelidonine seems to trigger multiple mechanisms in MCF-7 breast cancer cells. It induces both apoptosis and autophagy modes of cell death in a dose dependent manner. Alteration of expression levels of bax/bcl2, and dapk1a by increasing concentration of chelidonine approves switching the death mode from apoptosis induced by very low to autophagy by high concentrations of this compound. On the other hand, submicromolar concentrations of chelidonine strongly suppressed telomerase at both enzyme activity and hTERT transcriptional level. Long exposure of the cells to 50 nanomolar concentration of chelidonine considerably accelerated senescence. Altogether, chelidonine may provide a promising chemistry from nature to treat cancer. [ABSTRACT FROM AUTHOR]

Highlights: [•] Chelidonine, ingredient of Chelidonium majus extract, nano-encapsulated with PLGA. [•] Characterization of nano-chelidonine shows it to be a suitable drug carrier. [•] Nano-chelidonine exhibits better bio-distribution profile in liver tissue of mice. [•] Nano-chelidonine reduces cadmium induced oxidative stress better than chelidonine. [•] Signalling pathways and toxicity biomarkers for action of both drugs elucidated. [ABSTRACT FROM AUTHOR]

Highlights: [•] Chelidonine, major bioactive ingredient of Chelidonium majus. [•] PLGA encapsulated chelidonine nanoparticles prepared, characterized. [•] Nano-chelidonine enhanced apoptotic induction in HepG2 cells. [•] Nano-chelidonine exhibits greater bioavailability in mice than free chelidonine. [•] Anticancer potential makes nano-chelidonine for use in therapeutic oncology. [ABSTRACT FROM AUTHOR]

Abstract: Cancer cells often develop multidrug resistance (MDR) which is a multidimensional problem involving several mechanisms and targets. This study demonstrates that chelidonine and an alkaloid extract from Chelidonium majus, which contains protoberberine and benzo[c]phenanthridine alkaloids, has the ability to overcome MDR of different cancer cell lines through interaction with ABC-transporters, CYP3A4 and GST, by induction of apoptosis, and cytotoxic effects. Chelidonine and the alkaloid extract inhibited P-gp/MDR1 activity in a concentration-dependent manner in Caco-2 and CEM/ADR5000 and reversed their doxorubicin resistance. In addition, chelidonine and the alkaloid extract inhibited the activity of the drug modifying enzymes CYP3A4 and GST in a dose-dependent manner. The alkaloids induced apoptosis in MDR cells which was accompanied by an activation of caspase-3, -8,-6/9, and phosphatidyl serine (PS) exposure. cDNA arrays were applied to identify differentially expressed genes after treatment with chelidonine and the alkaloid extract. The expression analysis identified a common set of regulated genes related to apoptosis, cell cycle, and drug metabolism. Treatment of Caco-2 cells with 50μg/ml alkaloid extract and 50μM chelidonine for up to 48h resulted in a significant decrease in mRNA levels of P-gp/MDR1, MRP1, BCRP, CYP3A4, GST, and hPXR and in a significant increase in caspase-3 and caspase-8 mRNA. Thus, chelidonine is a promising model compound for overcoming MDR and for enhancing cytotoxicity of chemotherapeutics, especially against leukaemia cells. Its efficacy needs to be confirmed in animal models. [Copyright &y& Elsevier]