RESUMEN
ETHNOPHARMACOLOGY RELEVANCE: The plants of Amaryllidaceae family, such as Amaryllis belladonna L., have been used as herbal remedies for thousands of years to address various disorders, including diseases that might today be identified as cancer. AIM OF THE STUDY: The objective of this work was to evaluate the potential of three Amaryllidaceae alkaloids against four cancer cell lines. MATERIAL AND METHODS: The alkaloids lycorine, 1-O-acetylcaranine, and montanine were evaluated in vitro against colon adenocarcinoma cell line (HCT-116) and breast carcinoma cell lines (MCF-7, MDAMB231, and Hs578T). Computational experiments (target prediction and molecular docking) were conducted to gain a deeper comprehension of possible interactions between these alkaloids and potential targets associated with these tumor cells. RESULTS: Montanine presented the best results against HCT-116, MDAMB231, and Hs578T cell lines, while lycorine was the most active against MCF-7. In alignment with the target prediction outcomes and existing literature, four potential targets were chosen for the molecular docking analysis: CDK8, EGFR, ER-alpha, and dCK. The docking scores revealed two potential targets for the alkaloids with scores similar to co-crystallized inhibitors and substrates: CDK8 and dCK. A visual analysis of the optimal docked configurations indicates that the alkaloids may interact with some key residues in contrast to the other docked compounds. This observation implies their potential to bind effectively to both targets. CONCLUSIONS: In vitro and in silico results corroborate with data literature suggesting the Amaryllidaceae alkaloids as interesting molecules with antitumoral properties, especially montanine, which showed the best in vitro results against colorectal and breast carcinoma. More studies are necessary to confirm the targets and pharmaceutical potential of montanine against these cancer cell lines.
Asunto(s)
Alcaloides de Amaryllidaceae , Antineoplásicos Fitogénicos , Simulación del Acoplamiento Molecular , Humanos , Alcaloides de Amaryllidaceae/farmacología , Alcaloides de Amaryllidaceae/química , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Línea Celular Tumoral , Células MCF-7 , Amaryllidaceae/química , Células HCT116 , Simulación por Computador , Fenantridinas/farmacología , Fenantridinas/química , IsoquinolinasRESUMEN
BACKGROUND: Ang II induces hypertensive heart failure (HF) via hemodynamic and non-hemodynamic actions. Lycorine (LYC) is an alkaloid derived from Lycoris bulbs, and it possesses anti-cardiovascular disease-related activities. Herein, we explored the potential LYC-mediated regulation of Ang II-induced HF. METHODS: Over 4 weeks, we established a hypertensive HF mouse model by infusing Ang II into C57BL/6 mice using a micro-osmotic pump. For the final two weeks, mice were administered LYC via intraperitoneal injection. The LYC signaling network was then deduced using RNA sequencing. RESULTS: LYC administration strongly suppressed hypertrophy, myocardial fibrosis, and cardiac inflammation. As a result, it minimized heart dysfunction while causing no changes in blood pressure. The Nuclear Factor kappa B (NF-κB) network/phosphoinositol-3-kinase (PI3K)-protein kinase B (AKT) was found to be a major modulator of LYC-based cardioprotection using RNA sequencing study. We further confirmed that in cultured cardiomyocytes and mouse hearts, LYC reduced the inflammatory response and downregulated the Ang II-induced PI3K-AKT/NF-κB network. Moreover, PI3K-AKT or NF-κB axis depletion in cardiomyocytes completely abrogated the anti-inflammatory activities of LYC. CONCLUSION: Herein, we demonstrated that LYC safeguarded hearts in Ang II -stimulated mice by suppressing the PI3K-AKT/NF-κB-induced inflammatory responses. Given the evidence mentioned above, LYC is a robust therapeutic agent for hypertensive HF.
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Alcaloides de Amaryllidaceae , Angiotensina II , Ratones Endogámicos C57BL , FN-kappa B , Fenantridinas , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Animales , Alcaloides de Amaryllidaceae/farmacología , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fenantridinas/farmacología , Masculino , Transducción de Señal/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Ratones , Insuficiencia Cardíaca/tratamiento farmacológico , Remodelación Ventricular/efectos de los fármacos , Inflamación/tratamiento farmacológico , Miocitos Cardíacos/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Hipertensión/inducido químicamente , Modelos Animales de Enfermedad , Lycoris/química , MiocardioRESUMEN
BACKGROUND: Multiorgan dysfunction, especially sepsis-related multiorgan damage, remains a major cause of high mortality in the late stages of infection and a great clinical challenge. In recent years, natural drugs have received widespread attention because of their low cost, wide sources, high efficacy, low toxicity, and limited side effects. Lycorine, a natural compound extracted from Amaryllidaceae, exhibits multiple pharmacological activities, including in the regulation of autophagy and the induction of cancer cell apoptosis, and has anti-inflammatory, antifungal, antiviral, antimalarial, and antitumor activities. However, studies on lycorine have mainly focused on its antitumor properties, and research on its use for organ protection, especially in sepsis-related organ injury, is relatively limited. PURPOSE: To review and discuss the effects and mechanisms of lycorine in the treatment of multi-organ dysfunction, especially sepsis. METHODS: Literature searches in electronic databases, such as Web of Science, Science Direct, PubMed, Google Scholar, and Scopus, were performed using 'Lycorine', 'Amaryllidaceae', 'Pharmacology', 'Pharmacokinetics', 'Anti-inflammation', 'Autophagy', 'Apoptosis', 'Anti-microbial and anti-parasitic', 'Antitumor', 'Organ protection', and 'Sepsis' as keywords, the correlated literature was extracted and conducted from the databases mentioned above. RESULTS: By summarizing the progress made in existing research, we found that the general effects of lycorine involve the regulation of autophagy and the induction of cancer cell apoptosis, and anti-inflammatory, antifungal, antiviral, antimalarial, and antitumor effects; through these pathways, the compound can ameliorate organ damage. In addition, lycorine was found to have an important effect on organ damage in sepsis. CONCLUSION: Lycorine is a promising natural organ protective agent. This review will provide a new theoretical basis for the treatment of organ protection, especially in sepsis.
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Alcaloides de Amaryllidaceae , Amaryllidaceae , Antimaláricos , Alcaloides de Amaryllidaceae/farmacología , Antifúngicos/farmacología , Antimaláricos/farmacología , Antivirales/farmacología , Apoptosis , Fenantridinas/farmacologíaRESUMEN
BACKGROUND: Despite advances of surgery and neoadjuvant chemotherapy during the past few decades, the therapeutic efficacy of current therapeutic protocol for osteosarcoma (OS) is still seriously compromised by multi-drug resistance and severe side effects. Amplification of intracellular oxidative stress is considered as an effective strategy to induce cancer cell death. The purpose of this study was to develop a novel strategy that can amplify the intracellular oxidative stress for synergistic cascade cancer therapy. METHODS AND RESULTS: A novel nanocomposite, composed of folic acid (FA) modified mesoporous silica-coated gold nanostar (GNS@MSNs-FA) and traditional Chinese medicine lycorine (Ly), was rationally designed and developed. Under near-infrared (NIR) irradiation, the obtained GNS@MSNs-FA/Ly could promote a high level of ROS production via inducing mitochondrial dysfunction and potent endoplasmic reticulum (ER) stress. Moreover, glutathione (GSH) depletion during ER stress could reduce ROS scavenging and further enable efficient amplification of intracellular oxidative stress. Both in vitro and in vivo studies demonstrated that GNS@MSNs-FA/Ly coupled with NIR irradiation exhibited excellent antitumor efficacy without noticeable toxicity in MNNG/HOS tumor-bearing mice. CONCLUSION: All these results demonstrated that GNS@MSNs-FA/Ly coupled with NIR irradiation could dramatically amplify the intra-tumoral oxidative stress, exhibiting excellent antitumor ability without obvious systemic toxicity. Taken together, this promising strategy provides a new avenue for the effective cancer synergetic therapy and future clinical translation.
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Alcaloides de Amaryllidaceae/farmacología , Oro/química , Nanocompuestos/química , Neoplasias/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Fenantridinas/farmacología , Animales , Materiales Biocompatibles , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Estrés del Retículo Endoplásmico , Ácido Fólico , Humanos , Ratones , Microscopía Fluorescente , Mitocondrias , Nanocompuestos/uso terapéutico , Neoplasias/patología , Osteosarcoma , Especies Reactivas de Oxígeno , Dióxido de SilicioRESUMEN
BACKGROUND: Parkinson's disease (PD) is one of the most common neurodegenerative motor disorders, and is characterized by the presence of Lewy bodies containing misfolded α-synuclein (α-syn) and by selective degeneration of midbrain dopamine neurons. Studies have shown that upregulation of ubiquitin-proteasome system (UPS) activity promotes the clearance of aggregation-prone proteins such as α-syn and Tau, so as to alleviate the neuropathology of neurodegenerative diseases. PURPOSE: To identify and investigate lycorine as a UPS enhancer able to decrease α-syn in transgenic PD models. METHODS: Dot blot was used to screen α-syn-lowering compounds in an inducible α-syn overexpression cell model. Inducible wild-type (WT) and mutant α-syn-overexpressing PC12 cells, WT α-syn-overexpressing N2a cells and primary cultured neurons from A53T transgenic mice were used to evaluate the effects of lycorine on α-syn degradation in vitro. Heterozygous A53T transgenic mice were used to evaluate the effects of lycorine on α-syn degradation in vivo. mCherry-GFP-LC3 reporter was used to detect autophagy-dependent degradation. Ub-R-GFP and Ub-G76V-GFP reporters were used to detect UPS-dependent degradation. Proteasome activity was detected by fluorogenic substrate Suc-Leu-Leu-Val-Tyr-AMC (Suc-LLVY-AMC). RESULTS: Lycorine significantly promoted clearance of over-expressed WT and mutant α-syn in neuronal cell lines and primary cultured neurons. More importantly, 15 days' intraperitoneal administration of lycorine effectively promoted the degradation of α-syn in the brains of A53T transgenic mice. Mechanistically, lycorine accelerated α-syn degradation by activating cAMP-dependent protein kinase (PKA) to promote proteasome activity. CONCLUSION: Lycorine is a novel α-syn-lowering compound that works through PKA-mediated UPS activation. This ability to lower α-syn implies that lycorine has the potential to be developed as a pharmaceutical for the treatment of neurodegenerative diseases, such as PD, associated with UPS impairment and protein aggregations.
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Alcaloides de Amaryllidaceae/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Fenantridinas/farmacología , alfa-Sinucleína/metabolismo , Animales , Autofagia/efectos de los fármacos , Autofagia/fisiología , AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones Transgénicos , Fármacos Neuroprotectores/farmacología , Células PC12 , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Complejo de la Endopetidasa Proteasomal/metabolismo , Ratas , Ubiquitina/metabolismo , Regulación hacia Arriba/efectos de los fármacos , alfa-Sinucleína/genéticaRESUMEN
BACKGROUND: Neuroinflammation is defined as innate immune system activation in the central nervous system, and is a complex response involved in removing pathogens, toxic components, and dead cells by activating microglial cells. However, over-activated microglia have been implicated in the pathogenesis of neurodegenerative diseases, because they release large amounts of neurotoxic factors. Thus, inhibiting microglial activation may represent an attractive approach for preventing neuroinflammatory disorders. The objective of this study was to investigate the effect of narciclasine (NA) on lipopolysaccharide (LPS)-induced neuroinflammation by evaluating related markers and neurotoxic factors. METHODS: BV-2 cells were pre-incubated with NA at 0.1, 0.2, and 0.3 µM for 1h, and then co-treated with LPS for 12 h. Cellular medium and lysates were measured using a nitric oxide assay, enzyme-link immunosorbent assay (ELISA), western blotting, kinase activity assay, luciferase assay, and immunofluorescence assay. C57BL/6N mice were orally administered NA and intraperitoneally injected with LPS, and the cerebral cortex was examined using western blotting and immunofluorescence assays. RESULTS: NA showed novel pharmacological activity, inhibiting pro-inflammatory factors, including TNF-α, IL-6, IL-18, NO, and PGE2, but increasing the anti-inflammatory cytokines IL-10 and TGF-ß1 in LPS-induced microglial cells. Moreover, NA also attenuated the LPS-induced mRNA and proteins of iNOS and COX-2. The mechanistic study indicated that NA attenuates the secretion of pro-inflammatory factor by down-regulating the Akt/IKK/NF-κB and JNK signaling pathways, and directly inhibits the catalytic activity of IKKα/ß. Furthermore, we found that NA also reduced the expression of the microglial markers Iba-1, COX-2, and TNF-α in the mouse brain. CONCLUSION: NA inhibits the over-expression of pro-inflammatory factors but it promotes anti-inflammatory cytokines by down-regulating the Akt/IKK/NF-κB and JNK signaling pathways in experimental models. Thus, NA may be a potential candidate for relieving neuroinflammation.
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Alcaloides de Amaryllidaceae/farmacología , Antiinflamatorios/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Microglía/efectos de los fármacos , Fenantridinas/farmacología , Animales , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Inflamación , Lipopolisacáridos , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies worldwide. Metastasis is the major cause of death in patients with CRC. Lycorine, the phenanthridine alkaloid most commonly found in spp of the Amaryllidaceae family, has shown promising anticancer activities with minor side effects. However, the effects and the detailed mechanism of lycorine against metastasis of CRC remains unclear. STUDY DESIGN/METHODS: The purpose of this study was to investigate the effects of lycorine on CRC and characterize the molecular mechanisms observed in lycorine-treated CRC cells using RNA-sequencing. MTT assay, colony formation assay, acridine orange/ethidium bromide (AO/EB) staining and Annexin V-FITC/Propidium iodide (PI) staining were conducted to examine the effects of lycorine on cell proliferation and apoptosis in CRC cells. RNA sequencing, real-time PCR assays and western blot were performed. Migration and invasion abilities of lycorine-treated CRC cells were investigated by wound healing and transwell invasion assays. The mouse CRC lung metastasis model was established and was used to detect the effect of lycorine on CRC in vivo. RESULTS: Our results demonstrated that lycorine inhibited the proliferation and colony formation of CRC cells in a concentration-dependent manner. AO/EB staining and Annexin V-FITC/PI staining showed that lycorine induced apoptosis in a concentration-dependent manner. Lycorine also reduced lung metastasis of CRC in vivo. Moreover, transcriptomic analysis suggested that lycorine regulated the expression of 3556 genes. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway was implicated according to the differentially expressed genes (DEGs), and multiple pathways including those of mitogen-activated protein kinase (MAPK), relaxin, Ras, phosphatidylinositol 3kinase (PI3K)-protein kinase B (Akt) and Wnt/ß-catenin were selected by functional enrichment analyses. Furthermore, based on transcriptomic analysis, we found that the tumor necrosis factor (TNF) pathway and endoplasmic reticulum stress were responsible for lycorine-induced apoptosis. CONCLUSIONS: These results obtained in this study demonstrated that lycorine has the potential to suppress CRC in vitro and in vivo through the lycorine-regulated multiple signaling pathways.
Asunto(s)
Alcaloides de Amaryllidaceae/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Fenantridinas/farmacología , RNA-Seq , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/patología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Metástasis de la Neoplasia , Fosfatidilinositol 3-Quinasas/metabolismoRESUMEN
Lycorine, a natural compound isolated from the traditional Chinese medicinal herb Lycoris radiata, exhibits multiple pharmacological effects, such as anti-inflammatory, antiviral, and anticancer effects. Accumulating evidence also indicates that lycorine might hold the potential to treat age-associated Alzheimer's disease. However, whether lycorine is involved in delaying the onset of cellular senescence and its underlying mechanisms has not been determined. Here, we demonstrate that the salt of lycorine, lycorine hydrochloride, significantly suppressed stress-induced premature cellular senescence (SIPS) by ~2-fold, as determined by senescence-associated beta-galactosidase (SA-ß-gal) staining and the expression of p16 and p21. In addition, pretreating cells with lycorine hydrochloride significantly inhibited the expression of CXCL1 and IL1α, two factors of the senescence-associated secreted phenotype (SASP) in SIPS cells. Further experiments revealed that lycorine hydrochloride promoted both the homologous recombination (HR) and nonhomologous end joining (NHEJ) pathways of DNA double-strand break (DSB) repair. Mechanistic studies suggested that lycorine hydrochloride treatment promoted the transcription of SIRT1 and SIRT6, critical longevity genes positively regulating both HR and NHEJ repair pathways, thereby stimulating DSB repair and stabilizing genomes. Inhibiting SIRT1 enzymatic activity abrogated the protective effect of lycorine hydrochloride on delaying the onset of SIPS, repairing DSBs, and restoring genome integrity. In summary, our work indicates that lycorine hydrochloride might hold therapeutic potential for treating age-associated diseases or promoting healthy aging by stabilizing genomes.
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Alcaloides de Amaryllidaceae/farmacología , Medicamentos Herbarios Chinos/farmacología , Fenantridinas/farmacología , Células Cultivadas , Senescencia Celular/efectos de los fármacos , Senescencia Celular/genética , Humanos , Lycoris/química , Medicina Tradicional China , Estrés Oxidativo/efectos de los fármacosRESUMEN
INTRODUCTION: Macleaya cordata (Willd) R. Br. (Papaveraceae family) is a well-known traditional Chinese medicine used to treat muscle pain, inflamed wounds, and bee bites. Benzo[c]phenanthridine alkaloids are the main active ingredients in M. cordata. In this work, sanguinarine and chelerythrine were efficiently extracted and purified by ultrahigh-pressure extraction (UHPE) technique and pH-zone-refining counter-current chromatography (PZRCCC) from M. cordata. OBJECTIVE: To develop an efficient UHPE method followed by an efficient separation technique using PZRCCC for benzo[c]phenanthridine alkaloids from the study plant species, and to evaluate the study samples for anti-breast cancer activity. METHODOLOGY: The optimal extraction conditions were optimised as extraction pressure 200 MPa, extraction solvent 95% ethanol, solid-liquid ratio 1:30 (g/mL) and extraction time 2 min. A two-phase n-hexane/ethyl acetate/i-propanol/water (1:3:1.5:4.5, v/v) solvent system was optimised with 10 mmol triethylamine in the upper phase and 10 mmol trifluoroacetic acid in lower phase in PZRCCC. The sample loading was optimised as 2.50 g. Moreover, the samples were evaluated for anti-breast cancer activity later on. RESULTS: The 2.50 g sample loading yielded 0.45 g of sanguinarine and 0.59 g chelerythrine in one-step separation using PZRCCC. The anti-breast cancer activities of sanguinarine and chelerythrine were found stronger than positive control (vincristine 5.04 µg/mL) with half-maximal inhibitory concentration values of 0.96 and 3.00 µg/mL, respectively. CONCLUSION: This study showed that the established methods were efficient in extraction (UHPE) and separation (PZRCCC) of the sanguinarine and chelerythrine from M. cordata.
Asunto(s)
Alcaloides , Neoplasias , Papaveraceae , Alcaloides/farmacología , Animales , Cromatografía Líquida de Alta Presión , Distribución en Contracorriente , Concentración de Iones de Hidrógeno , Fenantridinas/farmacologíaRESUMEN
BACKGROUND: Highly effective novel treatments need to be developed to suppress emerging coronavirus (CoV) infections such as COVID-19. The RNA dependent RNA polymerase (RdRp) among the viral proteins is known as an effective antiviral target. Lycorine is a phenanthridine Amaryllidaceae alkaloid isolated from the bulbs of Lycoris radiata (L'Hér.) Herb. and has various pharmacological bioactivities including antiviral function. PURPOSE: We investigated the direct-inhibiting action of lycorine on CoV's RdRp, as potential treatment for emerging CoV infections. METHODS: We examined the inhibitory effect of lycorine on MERS-CoV, SARS-CoV, and SARS-CoV-2 infections, and then quantitatively measured the inhibitory effect of lycorine on MERS-CoV RdRp activity using a cell-based reporter assay. Finally, we performed the docking simulation with lycorine and SARS-CoV-2 RdRp. RESULTS: Lycorine efficiently inhibited these CoVs with IC50 values of 2.123 ± 0.053, 1.021 ± 0.025, and 0.878 ± 0.022 µM, respectively, comparable with anti-CoV effects of remdesivir. Lycorine directly inhibited MERS-CoV RdRp activity with an IC50 of 1.406 ± 0.260 µM, compared with remdesivir's IC50 value of 6.335 ± 0.731 µM. In addition, docking simulation showed that lycorine interacts with SARS-CoV-2 RdRp at the Asp623, Asn691, and Ser759 residues through hydrogen bonding, at which the binding affinities of lycorine (-6.2 kcal/mol) were higher than those of remdesivir (-4.7 kcal/mol). CONCLUSIONS: Lycorine is a potent non-nucleoside direct-acting antiviral against emerging coronavirus infections and acts by inhibiting viral RdRp activity; therefore, lycorine may be a candidate against the current COVID-19 pandemic.
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Alcaloides de Amaryllidaceae/farmacología , Antivirales/farmacología , Fenantridinas/farmacología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , SARS-CoV-2/efectos de los fármacos , Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Animales , Chlorocebus aethiops , Enlace de Hidrógeno , Coronavirus del Síndrome Respiratorio de Oriente Medio/efectos de los fármacos , Simulación del Acoplamiento Molecular , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/efectos de los fármacos , Células Vero , Proteínas ViralesRESUMEN
Lycorine is an Amaryllidaceae alkaloid that presents anti-Trichomonas vaginalis activity. T. vaginalis causes trichomoniasis, the most common non-viral sexually transmitted infection. The modulation of T. vaginalis purinergic signaling through the ectonucleotidases, nucleoside triphosphate diphosphohydrolase (NTPDase), and ecto-5'-nucleotidase represents new targets for combating the parasite. With this knowledge, the aim of this study was to investigate whether NTPDase and ecto-5'-nucleotidase inhibition by lycorine could lead to extracellular ATP accumulation. Moreover, the lycorine effect on the reactive oxygen species (ROS) production by neutrophils and parasites was evaluated as well as the alkaloid toxicity. The metabolism of purines was assessed by HPLC. ROS production was measured by flow cytometry. Cytotoxicity against epithelial vaginal cells and fibroblasts was tested, as well as the hemolytic effect of lycorine and its in vivo toxicity in Galleria mellonella larvae. Our findings showed that lycorine caused ATP accumulation due to NTPDase inhibition. The alkaloid did not affect the ROS production by T. vaginalis; however, it increased ROS levels in neutrophils incubated with lycorine-treated trophozoites. Lycorine was cytotoxic against vaginal epithelial cells and fibroblasts; conversely, it was not hemolytic neither exhibited toxicity against the in vivo model of G. mellonella larvae. Overall, besides having anti-T. vaginalis activity, lycorine modulates ectonucleotidases and stimulates neutrophils to secrete ROS. This mechanism of action exerted by the alkaloid could enhance the susceptibility of T. vaginalis to host immune cell, contributing to protozoan clearance.
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Alcaloides de Amaryllidaceae/farmacología , Amaryllidaceae/química , Antiprotozoarios/farmacología , Neutrófilos/metabolismo , Nucleósido-Trifosfatasa/antagonistas & inhibidores , Fenantridinas/farmacología , Extractos Vegetales/farmacología , Proteínas Protozoarias/antagonistas & inhibidores , Tricomoniasis/metabolismo , Trichomonas vaginalis/enzimología , 5'-Nucleotidasa/antagonistas & inhibidores , 5'-Nucleotidasa/metabolismo , Humanos , Neutrófilos/efectos de los fármacos , Nucleósido-Trifosfatasa/metabolismo , Proteínas Protozoarias/genética , Proteínas Protozoarias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Tricomoniasis/parasitología , Trichomonas vaginalis/efectos de los fármacos , Trichomonas vaginalis/crecimiento & desarrollo , Trichomonas vaginalis/metabolismo , Trofozoítos/efectos de los fármacos , Trofozoítos/enzimología , Trofozoítos/crecimiento & desarrollo , Trofozoítos/metabolismoRESUMEN
Plants of the Amaryllidaceae family are promising therapeutic tools for human diseases and have been used as alternative medicines. The specific secondary metabolites of this plant family, called Amaryllidaceae alkaloids (AA), have attracted considerable attention due to their interesting pharmacological activities. One of them, galantamine, is already used in the therapy of Alzheimer's disease as a long acting, selective, reversible inhibitor of acetylcholinesterase. One group of AA is the montanine-type, such as montanine, pancracine and others, which share a 5,11-methanomorphanthridine core. So far, only 14 montanine-type alkaloids have been isolated. Compared with other structural-types of AA, montanine-type alkaloids are predominantly present in plants in low concentrations, but some of them display promising biological properties, especially in vitro cytotoxic activity against different cancerous cell lines. The present review aims to summarize comprehensively the research that has been published on the Amaryllidaceae alkaloids of montanine-type.
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Alcaloides de Amaryllidaceae/química , Amaryllidaceae/química , Antineoplásicos Fitogénicos/química , Antiprotozoarios/química , Inhibidores de la Colinesterasa/química , Nootrópicos/química , Amaryllidaceae/metabolismo , Alcaloides de Amaryllidaceae/aislamiento & purificación , Alcaloides de Amaryllidaceae/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Antiprotozoarios/aislamiento & purificación , Antiprotozoarios/farmacología , Línea Celular Tumoral , Inhibidores de la Colinesterasa/aislamiento & purificación , Inhibidores de la Colinesterasa/farmacología , Galantamina/química , Galantamina/aislamiento & purificación , Galantamina/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/aislamiento & purificación , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Concentración 50 Inhibidora , Isoquinolinas/química , Isoquinolinas/aislamiento & purificación , Isoquinolinas/farmacología , Nootrópicos/aislamiento & purificación , Nootrópicos/farmacología , Fenantridinas/química , Fenantridinas/aislamiento & purificación , Fenantridinas/farmacología , Extractos Vegetales/química , Metabolismo SecundarioRESUMEN
Primary effusion lymphoma (PEL) is a subtype of non-Hodgkin lymphoma associated with infection by Kaposi sarcoma-associated herpes virus (KSHV). PEL is an aggressive disease with extremely poor prognosis when treated with conventional chemotherapy. Narciclasine, a natural product present in Amaryllidaceae family of flowering plants including daffodils, belongs to a class of molecules termed 'isocarbostyril alkaloid'. We have found that narciclasine displays preferential cytotoxicity towards PEL at low nanomolar concentrations and is approximately 10 and 100-fold more potent than its structural analogs lycoricidine and lycorine, respectively. Narciclasine arrested cell-cycle progression at the G1 phase and induced apoptosis in PEL, which is accompanied by activation of caspase-3/7, cleavage of PARP and increase in the surface expression of Annexin-V. Although narciclasine treatment resulted in a marked decrease in the expression of MYC and its direct target genes,time-course experiments revealed that MYC is not a direct target of narciclasine. Narciclasine treatment neither induces the expression of KSHV-RTA/ORF50 nor the production of infectious KSHV virions in PEL. Finally, narciclasine provides dramatic survival advantages to mice in two distinct mouse xenograft models of PEL. In conclusion, our results suggest that narciclasine could be a promising agent for the treatment of PEL.
Asunto(s)
Alcaloides de Amaryllidaceae/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Linfoma de Efusión Primaria/tratamiento farmacológico , Fenantridinas/farmacología , Extractos Vegetales/farmacología , Alcaloides de Amaryllidaceae/uso terapéutico , Animales , Antineoplásicos/uso terapéutico , Peso Corporal/efectos de los fármacos , Línea Celular Tumoral , Humanos , Linfoma de Efusión Primaria/patología , Ratones , Fenantridinas/uso terapéutico , Extractos Vegetales/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Fungal pathogenesis continues to be a burden to healthcare structures in both developed and developing nations. The gradual and irreversible loss of efficacies of existing antifungal medicines as well as the emergence of drug-resistant strains have contributed largely to this scenario. There is therefore a pressing need for new drugs from diverse structural backgrounds with improved potencies and novel modes of action to fortify or replace contemporary antifungal schedules. AIM: Alkaloids of the plant family Amaryllidaceae exhibit good growth inhibitory activities against several fungal pathogens. This review focuses on the mechanistic aspects of these antifungal activities. It achieves this by highlighting the molecular targets as well as structural features of Amaryllidaceae constituents which serve to enhance such action. METHODS: During the information gathering stage extensive use was made of the three database platforms; Google Scholar, SciFinder and Scopus. In most instances articles were accessed directly from journals licensed to the University of KwaZulu-Natal. In the absence of such proprietary agreements the respective corresponding authors were approached directly for copies of papers. RESULTS: Although several classes of molecules from the Amaryllidaceae have been probed for their antifungal effects, it is the key constituents lycorine and narciclasine which have together afforded the most profound mechanistic insights. These may be summarized as follows: (i) effects on the fungal cell wall and cell membrane; (ii) effects on morphology such as budding and hyphal growth; (iii) effects on fungal organelles such as ribosomes; (iv) effects on macromolecules such as DNA, RNA and proteins and; (v) identification of the active sites for these constituents. CONCLUSION: The key feature in the antifungal effects of Amaryllidaceae alkaloids is the inhibition of protein synthesis. This involved the inhibition of peptide bond formation by binding to yeast ribosomes via the 60S subunit. Related effects involved the inhibition of both DNA and RNA synthesis. These adverse effects were reflected morphologically on both the fungal cell wall and cell membrane. Such observations should prove useful in the chemotherapeutic arena should efforts shift towards the development of a clinical candidate.
Asunto(s)
Amaryllidaceae/química , Antifúngicos/química , Antifúngicos/farmacología , Alcaloides/química , Alcaloides/farmacología , Alcaloides de Amaryllidaceae/farmacología , Pared Celular/efectos de los fármacos , Fenantridinas/farmacología , Inhibidores de la Síntesis de la Proteína/química , Inhibidores de la Síntesis de la Proteína/farmacologíaRESUMEN
A new narciclasine glycoside, narciclasine-4-O-ß-D-xylopyranoside (1) was characterised along with four known alkaloids pancratistatin (2), 1-O-(3-hydroxybutyryl) pancratistatin (3), vittatine (4), 9-O-demethylgalanthine (5) from Zephyranthes minuta. Their structures were established on the basis of spectroscopic data analysis. The in vitro cytotoxic study of extract, fractions and isolated compounds against two human cancer cell lines (KB and SiHa) indicated the potential activity of extract and n-butanol fraction due to presence of active alkaloids pancratistatin, 1-O-(3-hydroxybutyryl) pancratistatin, lycorine and haemanthamine.
Asunto(s)
Alcaloides de Amaryllidaceae/aislamiento & purificación , Amaryllidaceae/química , Glicósidos/aislamiento & purificación , Fenantridinas/aislamiento & purificación , Alcaloides/química , Alcaloides/farmacología , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/farmacología , Glicósidos Cardíacos , Línea Celular Tumoral , Citotoxinas/aislamiento & purificación , Citotoxinas/farmacología , Glicósidos/química , Humanos , Isoquinolinas/farmacología , Fenantridinas/química , Fenantridinas/farmacología , Extractos Vegetales/químicaRESUMEN
Proteinaceous infectious particles causing mammalian transmissible spongiform encephalopathies or prions are being extensively studied. However due to their hazardous nature, the initial screening of potential anti-prion drugs is often made in a yeast-based screening system utilizing a well-characterized [PSI+] prion (amyloid formed by the translation termination factor Sup35p). In the [PSI+] prion screening system (white/red colony assay), the prion phenotype yields white colonies while addition of an anti-prion drug will yield red colonies. However, this system has some limitations. It is difficult to quantify the effectiveness of the anti-prion compound, the diffusion of the studied compound may affect the result, and the deficiency of glutathione in cells may prevent the formation of red pigment in cured cells. Therefore, alternative yeast prion screening systems are still needed. This article aims to present an alternative yeast-based system to evaluate anti-prion activity of chemical compounds. The method that was used is based on an artificial [LEU2+] prion created by fusing Leu2p with the prion-forming domain of Sup35p in Saccharomyces cerevisiae. Phenotypic analysis and semi-denaturating detergent agarose gel electrophoresis (SDD-AGE) confirmed the presence of the artificial [LEU2+] prion in yeast cells. This screening system verified the anti-prion activity of 3 drugs that were found to have been active in the white/red colony assay, while one compound (6-chlorotacrine) that was active in the white/red colony assay was found to be inactive in the [LEU2+] system. This new system also appears to be more sensitive than the white/red colony assay.
Asunto(s)
3-Isopropilmalato Deshidrogenasa/genética , Evaluación Preclínica de Medicamentos/métodos , Priones/efectos de los fármacos , Priones/genética , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Escherichia coli/genética , Guanabenzo/farmacología , Factores de Terminación de Péptidos/genética , Fenantridinas/farmacología , Fenotipo , Tacrina/análogos & derivados , Tacrina/síntesis química , Tacrina/farmacologíaRESUMEN
In this study, an extract from the bulbs of Cyrtanthus contractus showed strong anti-inflammatory activity in vitro. The extract was partially separated into 14 fractions and analyzed by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry metabolomics, and the correlation coefficients were calculated between biological activities and metabolite levels. As a result, the top-scoring metabolite narciclasine (1) is proposed as the active principle of C. contractus. This was confirmed by comparing the biological effect of crude extract with that of an authentic standard.
Asunto(s)
Alcaloides de Amaryllidaceae/farmacología , Amaryllidaceae/química , Antiinflamatorios no Esteroideos/farmacología , Metabolómica , Fenantridinas/farmacología , Alcaloides de Amaryllidaceae/química , Antiinflamatorios no Esteroideos/química , Adhesión Celular/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Molécula 1 de Adhesión Intercelular/efectos de los fármacos , Molécula 1 de Adhesión Intercelular/metabolismo , Espectrometría de Masas , Fenantridinas/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Raíces de Plantas/químicaRESUMEN
Coronaviruses (CoVs) act as cross-species viruses and have the potential to spread rapidly into new host species and cause epidemic diseases. Despite the severe public health threat of severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome CoV (MERS-CoV), there are currently no drugs available for their treatment; therefore, broad-spectrum inhibitors of emerging and endemic CoVs are urgently needed. To search for effective inhibitory agents, we performed high-throughput screening (HTS) of a 2,000-compound library of approved drugs and pharmacologically active compounds using the established genetically engineered human CoV OC43 (HCoV-OC43) strain expressing Renilla luciferase (rOC43-ns2Del-Rluc) and validated the inhibitors using multiple genetically distinct CoVs in vitro We screened 56 hits from the HTS data and validated 36 compounds in vitro using wild-type HCoV-OC43. Furthermore, we identified seven compounds (lycorine, emetine, monensin sodium, mycophenolate mofetil, mycophenolic acid, phenazopyridine, and pyrvinium pamoate) as broad-spectrum inhibitors according to their strong inhibition of replication by four CoVs in vitro at low-micromolar concentrations. Additionally, we found that emetine blocked MERS-CoV entry according to pseudovirus entry assays and that lycorine protected BALB/c mice against HCoV-OC43-induced lethality by decreasing viral load in the central nervous system. This represents the first demonstration of in vivo real-time bioluminescence imaging to monitor the effect of lycorine on the spread and distribution of HCoV-OC43 in a mouse model. These results offer critical information supporting the development of an effective therapeutic strategy against CoV infection.IMPORTANCE Currently, there is no approved therapy to treat coronavirus infection; therefore, broad-spectrum inhibitors of emerging and endemic CoVs are needed. Based on our high-throughput screening assay using a compound library, we identified seven compounds with broad-spectrum efficacy against the replication of four CoVs in vitro Additionally, one compound (lycorine) was found to protect BALB/c mice against HCoV-OC43-induced lethality by decreasing viral load in the central nervous system. This inhibitor might offer promising therapeutic possibilities for combatting novel CoV infections in the future.
Asunto(s)
Coronavirus Humano OC43/efectos de los fármacos , Coronavirus/efectos de los fármacos , Alcaloides de Amaryllidaceae/farmacología , Animales , Antivirales/farmacología , Línea Celular , Coronavirus/patogenicidad , Coronavirus Humano OC43/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Emetina/farmacología , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Ratones , Ratones Endogámicos BALB C , Coronavirus del Síndrome Respiratorio de Oriente Medio/efectos de los fármacos , Fenantridinas/farmacología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/efectos de los fármacosRESUMEN
Lycoris radiata (L'Her.) Herb. (L. radiata) was traditionally used as a folk medicine in China for treatment of Alzheimer's disease. However, the specific component responsible for its considerable toxicity remained unclear thus restricting its clinical trials. Narciclasine (NCS) was isolated from L. radiata and treatment of NCS for 72â¯h exhibited significant antiproliferative effects against L02, Hep G2, HT-29 and RAW264.7â¯cells. However, what needs to be emphasized is that at safe working concentrations of 0.001-0.016⯵M, administration of NCS for 24â¯h inhibited the mRNA expression of inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-É), interleukin-1beta (IL-1ß) and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-induced macrophages thereby suppressing production of nitric oxide (NO), IL-6, TNF-É and IL-1ß. NCS supplementation also inhibited nuclear factor-kappa B (NF-κB) activation by suppressing NF-κB P65 phosphorylation and nuclear translocation, IκBÉ degradation and phosphorylation, and IκKÉ/ß phosphorylation. The phosphorylation of c-Jun N-terminal kinase (JNK) and P38, and expression of COX-2 was also attenuated by NCS. These results suggested that NCS might exert anti-inflammatory effects through inhibiting NF-κB and mitogen-activated protein kinase (MAPK) pathways even at very low doses.
Asunto(s)
Alcaloides de Amaryllidaceae/farmacología , Antiinflamatorios/farmacología , Lycoris/química , Macrófagos/efectos de los fármacos , Fenantridinas/farmacología , Alcaloides de Amaryllidaceae/aislamiento & purificación , Alcaloides de Amaryllidaceae/toxicidad , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/toxicidad , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Citocinas/genética , Citocinas/metabolismo , Expresión Génica/efectos de los fármacos , Humanos , Inflamación/inducido químicamente , Lipopolisacáridos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , FN-kappa B/metabolismo , Fenantridinas/aislamiento & purificación , Fenantridinas/toxicidad , Componentes Aéreos de las Plantas/química , Células RAW 264.7 , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Cyclin-dependent kinases have emerged as important targets for cancer therapy. HSD992, containing a novel scaffold based on the tetrahydro-3H-pyrazolo[4,3-a]phenanthridine core, inhibits CDK2/3 but not other CDKs and also potently inhibits several cancer cell lines.