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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 265: 120403, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34562860

RESUMO

A new and highly sensitive and selective phenanthridine based sensor, 9-(7,8,13,14-tetrahydrodibenzo[a,i]phenanthridin-5-yl)benzo[h]quinolin-10-ol (PHBQ), was developed for the fluorescent ''turn-on'' detection of Th4+ ion in acetonitrile: water (8:2) medium. The fluorescence intensity of PHBQ diminished in the region of pH 1 to 3 and could be recovered by adjusting the pH to above 4. The sensor PHBQ showed distinct spectral changes in response to Th4+ ion over other competitive metal ions. The fluorescence displayed good linearity with the Th4+ concentration in the equivalence of 0-0.5 equivalents. The detection limit was calculated to be as low as 99 nM, which was less than that of previously reported sensors. The recognizing mechanism of PHBQ towards Th4+ was investigated in detail using HR-MS, NMR, and IR spectroscopy. The economically viable Whatman filter paper was fabricated with PHBQ to develop a paper-based fluorescence kit to detect the Th4+ in an aqueous medium efficiently. Furthermore, the application of sensor ligand in fluorescence imaging was studied in E-coli cells due to its minimal cytotoxicity and good optical properties. The obtained data suggest that the ligand PHBQ can be used as a fluorescent sensor for tracking Th4+ in multiple applications.


Assuntos
Corantes Fluorescentes , Água , Íons , Fenantridinas , Espectrometria de Fluorescência
2.
Poult Sci ; 100(10): 101404, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34478911

RESUMO

Duck tembusu virus (DTMUV) was firstly identified in 2010 in China; since then, it has caused enormous economic loss to breeding industry. Great efforts have been made to develop drugs and vaccines against DTMUV. However, current available vaccines or anti-DTMUV drugs are consistently inefficient. Hence, various more broadly effective drugs have become important for the treatment of DTMUV infection; among these, lycorine, one of the important sources of active alkaloids, is a promising example. Nevertheless, it is not known whether lycorine has any antiviral activities against DTMUV. Therefore, the purpose of the present study is to investigate the anti-DTMUV abilities of lycorine. The cytotoxicity of lycorine was evaluated on BHK-21 cells by CCK-8 assay, and its antiviral effect against DTMUV was examined by real-time PCR assays, virus titer determination, Western blot and immunofluorescence (IFA) assays, respectively. Furthermore, the underlying mechanisms of the anti-DTMUV effects of lycorine were also investigated. The results indicated that the highest nontoxicity concentration of lycorine on BHK-21 cells was 5 µM. Lycorine possessed the antiviral ability against DTMUV on BHK-21 cells, as demonstrated by the reduction of virus titers and copy numbers in vitro. Western blot and IFA analysis showed the inhibitory effect of lycorine on DTMUV envelope (E) protein expression. Moreover, using time-of-addition assays, we found that lycorine displays its antivirus and virucidal activities through blocking viral internalization and entry in vitro. Taken together, our findings firstly demonstrate the antiviral activities of lycorine against DTMUV, suggesting that lycorine can be a potential drug for the treatment of DTMUV infection.


Assuntos
Doenças das Aves Domésticas , Internalização do Vírus , Alcaloides de Amaryllidaceae , Animais , Antivirais/farmacologia , Galinhas , Patos , Flavivirus , Fenantridinas
3.
Eur J Pharm Sci ; 167: 106024, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34592462

RESUMO

The aim of the present work involved the development and evaluation of long-acting Isometamidium chloride (ISMM)-Docusate sodium (DS) complex loaded lipid nanoparticles (LA ISMM-DS LNP). The development involved screening various anionic complexing agents, including DS, dextran sulphate, and sodium alginate. Anionic DS was selected to synthesize hydrophobic ionic complex (ISMM-DS HIC), which was loaded into lipid nanoparticles (LA ISMM-DS LNP) by in situ complexation followed by the solvent evaporation method. 35-5-folds increase in the drug loading of hydrophilic cationic ISMM within nanoparticles was observed due to ISMM-DS HIC. The LA ISMM-DS LNP were non-hemolytic (0-2.52%), cytocompatible (80.6-47.5% cell viability), and enhanced THP-1 cellular uptake (2.3-folds higher) compared with free ISMM. The LA ISMM-DS LNP engender protracted in vivo plasma drug concentration for seven days with enhanced AUC0-ꝏ, MRT0-ꝏ, and t1/2, along with reduced Cl compared with free ISMM. Interestingly, the amount of ISMM was 2.9-, 4.2- and 2.0-folds higher in target reticuloendothelial (RES) organs like liver (Kupffer cells), spleen (spleenotropic macrophages and 15% T-lymphocytes), and lymph nodes (75% T-lymphocytes), respectively in LA ISMM-DS LNP group compared with free ISMM. Furthermore, LA ISMM-DS LNP caused higher peripheral blood mononuclear cells (PBMC) infiltration with diminished toxicity and inflammation. Therefore, the in vitro and in vivo studies predicted enhanced safety and efficacy of LA ISMM-DS LNP compared with free ISMM. To conclude, successfully developed LA ISMM-DS LNP would elicit a tremendous clinical potential for treatment and prevention against trypanosomiasis.


Assuntos
Leucócitos Mononucleares , Nanopartículas , Lipídeos , Fenantridinas , Distribuição Tecidual
4.
Molecules ; 26(18)2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34577030

RESUMO

Phenanthridinones are important heterocyclic frameworks present in a variety of complex natural products, pharmaceuticals and displaying wide range of pharmacological actions. Its structural importance has evoked a great deal of interest in the domains of organic synthesis and medicinal chemistry to develop new synthetic methodologies, as well as novel compounds of pharmaceutical interest. This review focuses on the synthesis of phenanthridinone scaffolds by employing aryl-aryl, N-aryl, and biaryl coupling reactions, decarboxylative amidations, and photocatalyzed reactions.


Assuntos
Fenantridinas/síntese química , Produtos Biológicos , Catálise , Técnicas de Química Sintética , Paládio , Fenantridinas/química
5.
Chemistry ; 27(59): 14778-14784, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34310792

RESUMO

Herein, we describe a gold-catalyzed cascade cyclization of Boc-protected benzylamines bearing two tethered alkyne moieties in a domino reaction initiated by a 6-endo-dig cyclization. The reaction was screened intensively, and the scope was explored, resulting in nine new Boc-protected dihydrobenzo[c]phenanthridines with yields of up to 98 %; even a π-extension and two bidirectional approaches were successful. Furthermore, thermal cleavage of the Boc group and subsequent oxidation gave substituted benzo[c]phenanthridines in up to quantitative yields. Two bidirectional approaches under the optimized conditions were successful, and the resulting π-extended molecules were tested as organic semiconductors in organic thin-film transistors.


Assuntos
Alcinos , Fenantridinas , Catálise , Ciclização , Estrutura Molecular
6.
Methods Mol Biol ; 2277: 289-297, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34080158

RESUMO

Mitochondrial reactive oxygen species (mtROS) and redox regulation play an important role in stem cell maintenance and cell fate decisions. Although changes in mtROS and redox homeostasis represent a physiological mechanism to drive stem cell commitment and differentiation, dysregulation of this system can lead to defects in stem cell maintenance and regenerative capacity. This chapter explains the methods used to assess mitochondrial superoxide levels and redox regulation in stem cell populations.


Assuntos
Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/análise , Células-Tronco/metabolismo , Animais , Perfilação da Expressão Gênica/métodos , Camundongos , Músculo Esquelético/citologia , Compostos Organofosforados/química , Oxirredução , Fenantridinas/química , Espécies Reativas de Oxigênio/metabolismo , Células-Tronco/fisiologia , Superóxido Dismutase/genética , Superóxidos/análise , Superóxidos/metabolismo , Proteína Desacopladora 2/genética
7.
Aging (Albany NY) ; 13(11): 15151-15163, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035183

RESUMO

Acute myocardial injury (AMI) is often secondary to sepsis, which is a life-threatening disease associated with severe cardiac inflammation. Narciclasine, a plant alkaloid isolated from different members of the Amaryllidaceae family, has been extensively characterized as an antitumor and anti-inflammatory compound. In addition, autophagy is critical for sepsis-induced myocardial injury. However, the role and mechanism of autophagy by which narciclasine confers cardioprotection are still unclear. The present study aimed to investigate the underlying mechanism by which narciclasine affects the pathogenesis of sepsis-induced myocardial injury. Narciclasine effectively attenuated LPS-induced myocardial inflammation in vitro and in vivo. In addition, narciclasine protected cardiac function and suppressed the expression of inflammatory cytokines in LPS-induced heart tissue. Furthermore, narciclasine upregulated LPS-induced autophagic activity, and the autophagy inhibitor 3-MA abrogated narciclasine-mediated protection against LPS-induced AMI. Importantly, narciclasine exerted an inhibitory effect on the JNK signaling pathway, and JNK activity was tightly associated with narciclasine-induced autophagy and the consequent protective effects during AMI. Taken together, our findings indicate that narciclasine protects against LPS-induced AMI by inducing JNK-dependent autophagic flux; hence, narciclasine may be an effective and novel agent for the clinical treatment of sepsis-induced myocardial injury.


Assuntos
Alcaloides de Amaryllidaceae/farmacologia , Autofagia , Miocárdio/patologia , Fenantridinas/farmacologia , Sepse/complicações , Adenina/análogos & derivados , Adenina/farmacologia , Adenina/uso terapêutico , Alcaloides de Amaryllidaceae/uso terapêutico , Animais , Autofagia/efeitos dos fármacos , Inflamação/patologia , Lipopolissacarídeos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Fenantridinas/uso terapêutico , Regulação para Cima/efeitos dos fármacos
8.
Phytomedicine ; 87: 153578, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34038839

RESUMO

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.


Assuntos
Alcaloides de Amaryllidaceae/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Doença de Parkinson/tratamento farmacológico , Fenantridinas/farmacologia , alfa-Sinucleína/metabolismo , Animais , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , AMP Cíclico/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Camundongos Transgênicos , Fármacos Neuroprotetores/farmacologia , Células PC12 , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ratos , Ubiquitina/metabolismo , Regulação para Cima/efeitos dos fármacos , alfa-Sinucleína/genética
9.
Sci Rep ; 11(1): 10408, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001990

RESUMO

The monofunctional platinum(II) complex, phenanthriplatin, acts by blocking transcription, but its regulatory effects on long-noncoding RNAs (lncRNAs) have not been elucidated relative to traditional platinum-based chemotherapeutics, e.g., cisplatin. Here, we treated A549 non-small cell lung cancer and IMR90 lung fibroblast cells for 24 h with either cisplatin, phenanthriplatin or a solvent control, and then performed microarray analysis to identify regulated lncRNAs. RNA22 v2 microRNA software was subsequently used to identify microRNAs (miRNAs) that might be suppressed by the most regulated lncRNAs. We found that miR-25-5p, -30a-3p, -138-5p, -149-3p, -185-5p, -378j, -608, -650, -708-5p, -1253, -1254, -4458, and -4516, were predicted to target the cisplatin upregulated lncRNAs, IMMP2L-1, CBR3-1 and ATAD2B-5, and the phenanthriplatin downregulated lncRNAs, AGO2-1, COX7A1-2 and SLC26A3-1. Then, we used qRT-PCR to measure the expression of miR-25-5p, -378j, -4516 (A549) and miR-149-3p, -608, and -4458 (IMR90) to identify distinct signaling effects associated with cisplatin and phenanthriplatin. The signaling pathways associated with these miRNAs suggests that phenanthriplatin may modulate Wnt/ß-catenin and TGF-ß signaling through the MAPK/ERK and PTEN/AKT pathways differently than cisplatin. Further, as some of these miRNAs may be subject to dissimilar lncRNA targeting in A549 and IMR90 cells, the monofunctional complex may not cause toxicity in normal lung compared to cancer cells by acting through distinct lncRNA and miRNA networks.


Assuntos
Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Compostos Organoplatínicos/farmacologia , Fenantridinas/farmacologia , RNA Longo não Codificante/metabolismo , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Fibroblastos , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , MicroRNAs/metabolismo , Compostos Organoplatínicos/uso terapêutico , Fenantridinas/uso terapêutico , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/genética , beta Catenina/metabolismo
10.
Bioorg Med Chem Lett ; 41: 128011, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33811993

RESUMO

Photodegradation of azilsartan produces a phenanthridine derivative, with its molecular structure determined by 1H and 13C NMR spectroscopy. This structure is confirmed by single-crystal X-ray diffraction and alternative synthesis. The phenanthridine ring formation is explained through the ring closure of an imidoylnitrene intermediate produced by decarboxylation of the 5-oxo-1,2,4-oxadiazole ring (oxadiazolone).


Assuntos
Benzimidazóis/química , Oxidiazóis/química , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Fenantridinas/síntese química , Fenantridinas/química , Processos Fotoquímicos
11.
Free Radic Biol Med ; 168: 214-225, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-33823245

RESUMO

Superoxide formation is a hallmark of cardiovascular disease with the involvement of different tissues and cell types. Identification of the cellular sources and subcellular localization of superoxide formation is important to understand the underlying disease pathomechanisms. In the present study, we used HPLC quantification of the superoxide-specific oxidation products of hydroethidine (HE or DHE) and its derivative hydropropidine (HPr+) for measurement of intra- and extracellular superoxide formation in isolated leukocytes and tissues of hypertensive rats. Superoxide generation by isolated leukocytes from human subjects as well as tissue samples of hypertensive rats (infusion of angiotensin-II for 7 days) was investigated using HPr+ and HE fluorescent probes with HPLC or plate reader detection. Both fluorescent dyes were used to test for intra- and extracellular superoxide formation using the supernatant or cell/tissue pellet for analysis. We demonstrate the correlation of impaired functional parameters (blood pressure, vascular function, and oxidative burst) and increased superoxide formation in different organ systems of hypertensive rats using the HPr+/HPLC method. In the cell model, the differences between HE and HPr+ and especially the advantage of the extracellular specificity of HPr+, due to its cell impermeability, became evident. Plate reader-based assays showed much higher background signal and were inferior to HPLC based methods. In conclusion, the HPr+/HPLC assay for superoxide determination is highly reliable in isolated immune cells and an animal model of arterial hypertension. In particular, the cell impermeability of HPr+ made it possible to differentiate between intra- and extracellular superoxide formation.


Assuntos
Hipertensão , Superóxidos , Animais , Cromatografia Líquida de Alta Pressão , Humanos , Hipertensão/induzido quimicamente , Fenantridinas , Compostos de Amônio Quaternário , Ratos
12.
J Org Chem ; 86(8): 5805-5819, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33793223

RESUMO

In this paper, an unprecedented selective synthesis of dihydrophenanthridine and phenanthridine derivatives through the cascade reactions of 2-arylanilines with alkynoates is presented. Mechanistic studies showed that the formation of the dihydrophenanthridine scaffold involves an initial C(sp2)-H alkenylation of 2-arylaniline with alkynoate followed by an intramolecular aza-Michael addition. When this reaction is carried out at elevated temperature, the in situ formed substituted dihydrophenanthridine readily undergoes a retro-Mannich-type reaction to give the corresponding phenanthridine through C-C bond cleavage. Compared with literature methods, this novel protocol has advantages such as easily obtainable substrates with a free amino group, pharmaceutically privileged products, cheap catalysts, and conveniently controllable selectivity.


Assuntos
Fenantridinas , Catálise
13.
Rev Bras Parasitol Vet ; 30(1): e020220, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33909833

RESUMO

Trypanosoma vivax infections cause nonspecific clinical signs in cattle associated with aparasitemic intervals, making disease diagnosis a challenge. In Brazil, diminazene aceturate and isometamidium chloride (ISM) are available to treat bovine trypanosomosis. The objective of this study was to follow-up, by molecular and serological techniques, dairy cattle naturally infected by T. vivax after ISM treatment. Thirty cattle naturally infected with T. vivax received two applications of ISM, at a dosage of 1.0 mg/kg intramuscularly, on days 0 and 150. For T. vivax diagnosis, EDTA-blood and serum samples were evaluated on 0, 7, 15, 30, 60, 90, 120, 150, 180, 210, and 240 days after treatment PCR, Loop-mediated isothermal amplification (LAMP) and ELISA. Animals with persistent detection of T. vivax DNA by both PCR and LAMP were found and continuous detection of anti-T. vivax IgG antibodies by ELISA, suggesting the presence of T. vivax resistance to ISM. The combination of LAMP and ELISA tests can prevent misdiagnosis of the parasite clearance in treated cattle, contributing to better disease control. This is the first experiment that demonstrates the persistence infection of T. vivax under ISM treatment in a natural infected herd and evidence of ISM chemotherapy-resistant T. vivax in Brazil.


Assuntos
Tripanossomicidas , Tripanossomíase Africana , Tripanossomíase Bovina , Animais , Brasil , Bovinos , Seguimentos , Técnicas de Diagnóstico Molecular , Técnicas de Amplificação de Ácido Nucleico , Fenantridinas , Tripanossomicidas/uso terapêutico , Trypanosoma vivax , Tripanossomíase Africana/veterinária , Tripanossomíase Bovina/diagnóstico , Tripanossomíase Bovina/tratamento farmacológico
14.
Angew Chem Int Ed Engl ; 60(22): 12446-12454, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-33719151

RESUMO

An emerging approach in the field of targeted drug delivery is the establishment of abiotic metal-triggered prodrug mechanisms that can control the release of bioactive drugs. Currently, the design of prodrugs that use abiotic metals as a trigger relies heavily on uncaging strategies. Here, we introduce a strategy based on the gold-catalyzed activation of a phenanthridinium-based prodrug via hydroamination under physiological conditions. To make the prodrug strategy biocompatible, a gold artificial metalloenzyme (ArM) based on human serum albumin, rather than the free gold metal complex, was used as a trigger for prodrug activation. The albumin-based gold ArM protected the catalytic activity of the bound gold metal even in the presence of up to 1 mM glutathione in vitro. The drug synthesized via the gold ArM exerted a therapeutic effect in cell-based assays, highlighting the potential usefulness of the gold ArM in anticancer applications.


Assuntos
Ouro/química , Fenantridinas/química , Pró-Fármacos/química , Células A549 , Aminação , Catálise , Sobrevivência Celular/efeitos dos fármacos , Ciclização , Glutationa/química , Humanos , Metaloproteínas/química , Metaloproteínas/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Albumina Sérica/química
15.
Phytomedicine ; 85: 153530, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33761445

RESUMO

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.


Assuntos
Alcaloides de Amaryllidaceae/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Fenantridinas/farmacologia , RNA-Seq , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Fosfatidilinositol 3-Quinases/metabolismo
16.
Phytomedicine ; 85: 153540, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33773188

RESUMO

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.


Assuntos
Alcaloides de Amaryllidaceae/farmacologia , Anti-Inflamatórios/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Microglia/efeitos dos fármacos , Fenantridinas/farmacologia , Animais , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Inflamação , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
17.
J Enzyme Inhib Med Chem ; 36(1): 707-718, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33663315

RESUMO

In discovery of novel HDAC inhibitory with anticancer potency, pharmacophores of phenanthridine were introduced to the structure of HDAC inhibitors. Fatty and aromatic linkers were evaluated for their solubility and activity. Both enzyme inhibitory and in vitro antiproliferative (against U937 cells) screening results revealed better activities of compounds with aromatic linker than molecules with fatty linker. Compared with SAHA (IC50 values of 1.34, 0.14, 2.58, 0.67 and 18.17 µM), molecule Fb-4 exhibited 0.87, 0.09, 0.32, 0.34 and 17.37 µM of IC50 values against K562, U266, MCF-7, U937 and HEPG2 cells, respectively. As revealed by cell cycle and apoptotic analysis, induction of G2/M phase arrest and apoptosis plays an important role in the inhibition of MCF-7 cells by Fb-4. Generally, a potent HDAC inhibitor was developed in the present study which could be utilised as a lead compound for further anticancer drug design.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Fenantridinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Estrutura Molecular , Fenantridinas/síntese química , Fenantridinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
18.
Oncol Rep ; 45(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33649853

RESUMO

Colorectal cancer (CRC) is a life­threatening malignant tumor of the digestive tract. Diverse gene mutations and complicated alterations to the signaling pathways in CRC lead to heterogeneity in response to chemotherapy. Moreover, anticancer drugs for CRC chemotherapy are limited due to adverse events. Therefore, developing more effective, tolerable and safe drugs for the treatment of CRC is important. The present study aimed to investigate the effect of lycorine on human CRC cell proliferation, migration, invasion, apoptosis, cell cycle distribution, as well as the underlying molecular mechanism. The crystal violet staining and MTT assay results demonstrated that lycorine suppressed cell proliferation in a dose­ and time­dependent manner in the three CRC cell lines, HCT116, LoVo and SW480. Similarly, verified by performing wound healing and Transwell assays, lycorine significantly inhibited HCT116 and LoVo cell migration and invasion in vitro compared with the control group. In LoVo cells, the protein expression levels of matrix metallopeptidases, snail family transcriptional repressor 1, Vimentin and N­cadherin were significantly downregulated, whereas the protein expression levels of E­cadherin were significantly upregulated by lycorine treatment compared with the control group. The Hoechst 33258 staining and flow cytometry assay results indicated that lycorine mediated its cytostatic effect on CRC cells potentially via inducing cell cycle arrest, but not apoptosis. Compared with the control group, lycorine significantly induced HCT116 cell cycle arrest at the G2/M phase, but significantly induced LoVo cell cycle arrest at the S and G2/M phases. Furthermore, lycorine significantly downregulated the protein expression levels of cyclin D1 and cyclin E1, but significantly increased p21 and Smad4 protein expression levels in HCT116 and LoVo cells compared with the control group. The intracellular reactive oxygen species (ROS) measurement results also indicated that compared with the control group, lycorine significantly induced ROS accumulation, and increased phosphorylated­p38 expression levels and AKT phosphorylation. Collectively, the present study suggested that lycorine might induce cell cycle arrest and exert cytostatic effects potentially via activating ROS/p38 and AKT signaling pathways in CRC cells.


Assuntos
Alcaloides de Amaryllidaceae/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fenantridinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Células HCT116 , Humanos , Invasividade Neoplásica
19.
J Nat Prod ; 84(4): 1175-1184, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33760626

RESUMO

Porcine epidemic diarrhea virus (PEDV) has become increasingly problematic around the world, not only for its hazards to livestock but also due to the possibility that it is a zoonotic disease. Although vaccine therapy has made some progress toward PEDV control, additional effective therapeutic strategies against PEDV are needed, such as the development of chemotherapeutic agents. The aim of this work was to identify novel anti-PEDV agents by designing and synthesizing a series of phenanthridine derivatives. Among them, three compounds (compounds 1, 2, and 4) were identified as potent anti-PEDV agents exhibiting suppression of host cell heat shock cognate 70 (Hsc70) expression. Mechanism studies revealed that host Hsc70 is involved in the replication of PEDV, and its expression can be suppressed by destabilization of the mRNA, resulting in inhibition of PEDV replication. Activity against PEDV in vivo in PEDV-infected piglets suggested that phenanthridine derivatives are the first host-acting potential anti-PEDV agents.


Assuntos
Antivirais/farmacologia , Proteínas de Choque Térmico HSC70/metabolismo , Fenantridinas/farmacologia , Vírus da Diarreia Epidêmica Suína/efeitos dos fármacos , Animais , Antivirais/síntese química , Linhagem Celular , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/veterinária , Desenho de Fármacos , Estrutura Molecular , Fenantridinas/síntese química , Suínos
20.
Oxid Med Cell Longev ; 2021: 6667355, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33747349

RESUMO

We previously found that marine sponge-derived manoalide induced antiproliferation and apoptosis of oral cancer cells as well as reactive species generations probed by dichloro-dihydrofluorescein diacetate (DCFH-DA) and MitoSOX Red. However, the sources of cellular and mitochondrial redox stresses and the mutual interacting effects between these redox stresses and apoptosis remain unclear. To address this issue, we examined a panel of reactive species and used the inhibitors of cellular reactive species (N-acetylcysteine (NAC)), mitochondrial reactive species (MitoTEMPO), and apoptosis (Z-VAD-FMK; ZVAD) to explore their interactions in manoalide-treated oral cancer Ca9-22 and CAL 27 cells. Hydroxyl (˙OH), nitrogen dioxide (NO2˙), nitric oxide (˙NO), carbonate radical-anion (CO3 ˙-), peroxynitrite (ONOO-), and superoxide (O2 ˙-) were increased in oral cancer cells following manoalide treatments in terms of fluorescence staining and flow cytometry. Cellular reactive species (˙OH, NO2 ·, ˙NO, CO3 ˙-, and ONOO-) as well as cellular and mitochondrial reactive species (O2 ˙-) were induced in oral cancer cells following manoalide treatment for 6 h. NAC, MitoTEMPO, and ZVAD inhibit manoalide-induced apoptosis in terms of annexin V and pancaspase activity assays. Moreover, NAC inhibits mitochondrial reactive species and MitoTEMPO inhibits cellular reactive species, suggesting that cellular and mitochondrial reactive species can crosstalk to regulate each other. ZVAD shows suppressing effects on the generation of both cellular and mitochondrial reactive species. In conclusion, manoalide induces reciprocally activation between cellular and mitochondrial reactive species and apoptosis in oral cancer cells.


Assuntos
Apoptose/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Espécies Reativas de Oxigênio/metabolismo , Terpenos/farmacologia , Acetilcisteína/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Etídio/análogos & derivados , Etídio/metabolismo , Fluoresceínas/metabolismo , Humanos , Mitocôndrias/efeitos dos fármacos , Oligopeptídeos/farmacologia , Compostos Organofosforados/farmacologia , Fenantridinas/metabolismo , Piperidinas/farmacologia
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