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1.
Life Sci ; 284: 119893, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34454947

RESUMO

AIMS: Tumor cells metastasis as well as proliferation are important factors that can substantially determines the prognosis of cancer. In particular, epithelial-mesenchymal transition (EMT) is key phenomena which can cause tumor cell transition into other organs by promoting the disruption of the cell-cell junctions. Because oxymatrine (OMT) have been reported to attenuate the tumor growth, we investigated whether OMT can down-regulate EMT process in tumor cells. We also focused on transforming growth factor-ß (TGF-ß)-induced EMT process because EMT process can be significantly induced by this growth factor. MAIN METHODS: The cell viability was measured by MTT and real time cell analysis (RTCA) assay. The expression levels of various proteins involved in the regulation of EMT and Akt/mTOR/PI3K signaling pathway were evaluated by Western blot analysis. mRNA levels of several important EMT markers were analyzed by reverse transcription polymerase chain reaction (RT-PCR). The effects of OMT on the cellular invasion and migration were evaluated by RTCA, wound healing assay, and boyden chamber assays. KEY FINDINGS: OMT suppressed the expression of both constitutive and TGF-ß-induced mesenchymal markers, such as fibronectin, vimentin, MMP-9, MMP-2, N-cadherin, Twist, and Snail, but induced the levels of epithelial markers. Moreover, OMT down-regulated oncogenic PI3K/Akt/mTOR pathways which lead to a significant attenuation of invasive and migratory potential of lung cancer cells. SIGNIFICANCE: Overall, our study established a novel anti-metastatic role of OMT against human lung cancer cells.


Assuntos
Alcaloides/farmacologia , Transição Epitelial-Mesenquimal , Neoplasias Pulmonares/patologia , Quinolizinas/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Alcaloides/química , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Modelos Biológicos , Invasividade Neoplásica , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinolizinas/química , Proteínas Quinases S6 Ribossômicas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Fator de Crescimento Transformador beta/farmacologia
2.
Phytochemistry ; 190: 112842, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34214924

RESUMO

A phytochemical investigation on the flowers of Sophora davidii resulted in the isolation of three unusual matrine-adenine hybrids, sophovicines A-C, together with biogenetically related analogue sophocarpine. Their structures and absolute configurations were determined by NMR analysis, single-crystal X-ray diffraction, and electronic circular dichroism (ECD) data. Since sophovicines represent the first example of matrine-adenine hybrids, a putative biosynthetic pathway toward sophovicines A-C was proposed. In addition, computational molecular modeling suggested that compounds sophovicines B and C may have potent activities against human cytomegalovirus (HCMV). So, the inhibit effects of isolates on HCMV were evaluated. The results show that sophovicines B and C can inhibit HCMV replication effectively with IC50 values of 7.12 and 7.32 µM, respectively.


Assuntos
Sophora , Adenina/farmacologia , Alcaloides , Citomegalovirus , Humanos , Estrutura Molecular , Quinolizinas/farmacologia
3.
Cell Mol Biol Lett ; 26(1): 19, 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006215

RESUMO

BACKGROUND: Some natural compounds inhibit cancer cell growth in various cancer cell lines with fewer side effects than traditional chemotherapy. Here, we explore the pharmacological effects and mechanisms of worenine (isolated from Coptis chinensis) against colorectal cancer. METHODS: The effects of worenine on colorectal cancer cell proliferation, colony formation and cell cycle distribution were measured. Glycolysis was investigated by examining glucose uptake and consumption, lactate production, and the activities and expressions of glycolysis enzymes (PFK-L, HK2 and PKM2). HIF-1α was knocked down and stimulated in vitro to investigate the underlying mechanisms. RESULTS: Worenine somewhat altered the glucose metabolism and glycolysis (Warburg effect) of cancer cells. Its anti-cancer effects and capability to reverse the Warburg effect were similar to those of HIF-1α siRNA and weakened by deferoxamine (an HIF-1α agonist). CONCLUSION: It is suggested that worenine targets HIF-1α to inhibit colorectal cancer cell growth, proliferation, cell cycle progression and the Warburg effect.


Assuntos
Benzodioxóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Quinolizinas/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Proteólise/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/metabolismo
4.
Microb Pathog ; 156: 104926, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33964419

RESUMO

Mounting evidence revealed the negative effects of abuse of antibiotic including the induction of decreased immunity and dysbacteriosis. Matrine displayed multiple beneficial effects such as anti-inflammatory, antiviral and antibacterial, but studies of its influence on gut microbiota are still insufficient to report. Here, the present study was conducted to investigate the influence of matrine on the gut microbiota of mice and amoxicillin was used as a positive control. A total of 21 cecal samples were obtained from seven groups for high-throughput sequencing analysis based on V3-V4 variable region of 16S rRNA genes. Results revealed that the diversity and abundance of gut microbiota in mice gradually decreased with the increase of the concentration of amoxicillin, whereas matrine administration did not effect the intestinal microbial community structure. Additionally, amoxicillin and matrine supplementation also caused significant changes in the relative abundance of some intestinal bacteria. Specifically, the ratio of Klebsiella and Corynebacterium_1, Bacteroides and Parasutterella in the amoxicillin treated-group were increased as compared to the control group, whereas Muribaculaceae_unclassified, Alistipes and Lactobacillus were significantly decreased. Conversely, matrine administration significantly increased the proportion of beneficial bacteria such as Ruminiclostridium_9, Lachnospiraceae_NK4A136_group and Ruminococcaceae_unclassified. In conclusion, amoxicillin administration could change the microbial community composition and structure by increasing the proportion of pathogenic to beneficial bacteria, whereas matrine could increase the number of beneficial bacteria. Moreover, this study provides a theoretical basis for finding alternatives to antibiotics to decrease bacterial resistance and intestinal flora imbalance.


Assuntos
Microbioma Gastrointestinal , Microbiota , Alcaloides , Animais , Camundongos , Quinolizinas/farmacologia , RNA Ribossômico 16S/genética
5.
Phytomedicine ; 87: 153580, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34029939

RESUMO

BACKGROUNDS: Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancer with high metastasis and recurrence rates. Hypoxia-induced miRNAs and HIF-1α are demonstrated to play essential roles in tumor metastasis. Matrine (C15H24N2O), an alkaloid extracted from Sophora flavescens Aiton, has been used as adjuvant therapy for liver cancer in China. The anti-metastasis effects of matrine on HCC and the underlying mechanisms remain poorly understood. PURPOSE: We aimed to investigate the effects of matrine on metastasis of HCC both in vitro and in vivo, and explored whether miR-199a-5p and HIF-1α are involved in the action of matrine. METHODS: MTT method, colony formation, wound healing and matrigel transwell assays were performed to evaluate the effects of matrine on cell proliferation, migration and invasion. Nude mice xenograft model and immunohistochemistry (IHC) assay were employed to investigate the anti-metastatic action of matrine in vivo. Quantitative real-time PCR, western blot and dual luciferase reporter assay were conducted to determine the underlying mechanisms of matrine. RESULTS: Matrine exerted stronger anti-proliferative action on Bel7402 and SMMC-7721 cells under hypoxia than that in normoxia. Both matrine and miR-199a-5p exhibited significant inhibitory effects on migration, invasion and EMT in Bel7402 and SMMC-7721 cells under hypoxia. Further study showed that miR-199a-5p was downregulated in HCC cell lines, and this microRNA was identified to directly target HIF-1α, resulting in decreased HIF-1α expression. Matrine induced miR-199a-5p expression, decreased HIF-1α expression and inhibited metastasis of Bel7402 and SMMC-7721 cells, while miR-199a-5p knockdown reversed the inhibitory effects of matrine on cell migration, invasion, EMT and HIF-1α expression. In vivo, matrine showed significant anti-metastatic activity in the nude mouse xenograft model. H&E and IHC analysis indicated that lung and liver metastasis nodules were reduced, and the protein expression of HIF-1α and Vimentin were significantly decreased by i.p injection of matrine. CONCLUSIONS: Matrine exhibits significant anti-metastatic effect on HCC, which is attributed to enhanced miR-199a-5p expression and subsequently impaired HIF-1α signaling and EMT. These findings suggest that miR-199a-5p is a potential therapeutic target of HCC, and matrine may represent a promising anti-metastatic medication for HCC therapy.


Assuntos
Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Quinolizinas/farmacologia , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/patologia , Camundongos Nus , MicroRNAs/genética , Recidiva Local de Neoplasia , Sophora/química , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Cell Mol Med ; 25(12): 5707-5720, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34002930

RESUMO

To investigate the therapeutic effects of phellodendrine in ulcerative colitis (UC) through the AMPK/mTOR pathway. Volunteers were recruited to observe the therapeutic effects of Compound Cortex Phellodendri Liquid (Huangbai liniment). The main components of Compound Cortex Phellodendri Liquid were analysed via network pharmacology. The target of phellodendrine was further analysed. Caco-2 cells were cultured, and H2 O2 was used to stimulate in vitro cell model. Expression levels of LC3, AMPK, p-AMPK, mTOR and p-mTOR were detected via Western blotting and through immunofluorescence experiments. The therapeutic effects of phellodendrine were analysed via expression spectrum chip sequencing. The sequencing of intestinal flora further elucidated the therapeutic effects of phellodendrine. Compared with the control group, Compound Cortex Phellodendri Liquid could substantially improve the healing of intestinal mucosa. Network pharmacology analysis revealed that phellodendrine is the main component of Compound Cortex Phellodendri Liquid. Moreover, this alkaloid targets the AMPK signalling pathway. Results of animal experiments showed that phellodendrine could reduce the intestinal damage of UC compared with the model group. Findings of cell experiments indicated that phellodendrine treatment could activate the p-AMPK /mTOR signalling pathway, as well as autophagy. Expression spectrum chip sequencing showed that treatment with phellodendrine could promote mucosal healing and reduce inflammatory responses. Results of intestinal flora detection demonstrated that treatment with phellodendrine could increase the abundance of flora and the content of beneficial bacteria. Phellodendrine may promote autophagy by regulating the AMPK-mTOR signalling pathway, thereby reducing intestinal injury due to UC.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia , Colite Ulcerativa/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Quinolizinas/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Adulto , Animais , Estudos de Casos e Controles , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Transdução de Sinais , Serina-Treonina Quinases TOR/genética
7.
Sci Rep ; 11(1): 9520, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947942

RESUMO

Inflammatory demyelination and axonal injury of the optic nerve are hallmarks of optic neuritis (ON), which often occurs in multiple sclerosis and is a major cause of visual disturbance in young adults. Although a high dose of corticosteroids can promote visual recovery, it cannot prevent permanent neuronal damage. Novel and effective therapies are thus required. Given the recently defined capacity of matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae flavescens, in immunomodulation and neuroprotection, we tested in this study the effect of matrine on rats with experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. MAT administration, started at disease onset, significantly suppressed optic nerve infiltration and demyelination, with reduced numbers of Iba1+ macrophages/microglia and CD4+ T cells, compared to those from vehicle-treated rats. Increased expression of neurofilaments, an axon marker, reduced numbers of apoptosis in retinal ganglion cells (RGCs). Moreover, MAT treatment promoted Akt phosphorylation and shifted the Bcl-2/Bax ratio back towards an antiapoptotic one, which could be a mechanism for its therapeutic effect in the ON model. Taken as a whole, our results demonstrate that MAT attenuated inflammation, demyelination and axonal loss in the optic nerve, and protected RGCs from inflammation-induced cell death. MAT may therefore have potential as a novel treatment for this disease that may result in blindness.


Assuntos
Alcaloides/farmacologia , Apoptose/efeitos dos fármacos , Neurite Óptica/tratamento farmacológico , Quinolizinas/farmacologia , Células Ganglionares da Retina/efeitos dos fármacos , Animais , Axônios/efeitos dos fármacos , Axônios/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/metabolismo , Neurite Óptica/metabolismo , Plantas Medicinais/química , Ratos , Ratos Wistar , Células Ganglionares da Retina/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Bioorg Med Chem Lett ; 43: 128104, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33984477

RESUMO

To explore natural-product-based insecticide candidates, and high value-added application of natural plants in agriculture, a series of twin compounds were prepared from two natural products podophyllotoxin and cytisine, which are isolated from the plants Podophyllum hexandrum and Thermopsis lanceolata, respectively. Compounds IIa (X = Cl, Y = R1 = R2 = H), IIIc (X = Y = R1 = R2 = Cl) and IVd (X = R1 = R2 = Br, Y = H) exhibited >2-fold potent insecticidal activity of podophyllotoxin against armyworm with FMRs greater than 60%. SARs were also observed. It is noteworthy that the idea of twin insecticides was addressed for the first time. We hope this idea will be conducive to design new twin insecticidal agents, and lay the foundation for future high value-added application of the plants P. hexandrum and T. lanceolata as potentially botanical pesticides in agriculture.


Assuntos
Alcaloides/farmacologia , Inseticidas/farmacologia , Mariposas/efeitos dos fármacos , Podofilotoxina/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Animais , Azocinas/química , Azocinas/isolamento & purificação , Azocinas/farmacologia , Relação Dose-Resposta a Droga , Fabaceae/química , Inseticidas/química , Inseticidas/isolamento & purificação , Estrutura Molecular , Podofilotoxina/química , Podofilotoxina/isolamento & purificação , Podophyllum/química , Quinolizinas/química , Quinolizinas/isolamento & purificação , Quinolizinas/farmacologia , Relação Estrutura-Atividade
9.
Brief Bioinform ; 22(5)2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-33876189

RESUMO

Targeting tumor microenvironment (TME), such as immune checkpoint blockade (ICB), has achieved increased overall response rates in many advanced cancers, such as non-small cell lung cancer (NSCLC), however, only in a fraction of patients. To improve the overall and durable response rates, combining other therapeutics, such as natural products, with ICB therapy is under investigation. Unfortunately, due to the lack of systematic methods to characterize the relationship between TME and ICB, development of rational immune-combination therapy is a critical challenge. Here, we proposed a systems pharmacology strategy to identify resistance regulators of PD-1/PD-L1 blockade and develop its combinatorial drug by integrating multidimensional omics and pharmacological methods. First, a high-resolution TME cell atlas was inferred from bulk sequencing data by referring to a high-resolution single-cell data and was used to predict potential resistance regulators of PD-1/PD-L1 blockade through TME stratification analysis. Second, to explore the drug targeting the resistance regulator, we carried out the large-scale target fishing and the network analysis between multi-target drug and the resistance regulator. Finally, we predicted and verified that oxymatrine significantly enhances the infiltration of CD8+ T cells into TME and is a powerful combination agent to enhance the therapeutic effect of anti-PD-L1 in a mouse model of lung adenocarcinoma. Overall, the systems pharmacology strategy offers a paradigm to identify combinatorial drugs for ICB therapy with a systems biology perspective of drug-target-pathway-TME phenotype-ICB combination.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Quimioterapia Combinada , Feminino , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/genética , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos Endogâmicos C57BL , Extratos Vegetais/farmacologia , Quinolizinas/farmacologia , Quinolizinas/uso terapêutico , Sophora/química , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
10.
Biomolecules ; 11(3)2021 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805605

RESUMO

Cystic fibrosis is a monogenic, autosomal, recessive disease characterized by an alteration of chloride transport caused by mutations in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene. The loss of Phe residue in position 508 (ΔF508-CFTR) causes an incorrect folding of the protein causing its degradation and electrolyte imbalance. CF patients are extremely predisposed to the development of a chronic inflammatory process of the bronchopulmonary system. When the cells of a tissue are damaged, the immune cells are activated and trigger the production of free radicals, provoking an inflammatory process. In addition to routine therapies, today drugs called correctors are available for mutations such as ΔF508-CFTR as well as for others less frequent ones. These active molecules are supposed to facilitate the maturation of the mutant CFTR protein, allowing it to reach the apical membrane of the epithelial cell. Matrine induces ΔF508-CFTR release from the endoplasmic reticulum to cell cytosol and its localization on the cell membrane. We now have evidence that Matrine and Lumacaftor not only restore the transport of mutant CFTR protein, but probably also counteract the inflammatory process by improving the course of the disease.


Assuntos
Alcaloides/uso terapêutico , Aminopiridinas/uso terapêutico , Benzodioxóis/uso terapêutico , Fibrose Cística/tratamento farmacológico , Inflamação/patologia , Quinolizinas/uso terapêutico , Células A549 , Alcaloides/farmacologia , Aminopiridinas/farmacologia , Benzodioxóis/farmacologia , Morte Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Fibrose Cística/patologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Modelos Biológicos , Estresse Oxidativo/efeitos dos fármacos , Quinolizidinas/farmacologia , Quinolizinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
11.
Front Immunol ; 12: 640778, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33912166

RESUMO

The etiology of multiple sclerosis (MS) is not clear, and the treatment of MS presents a great challenge. This study aimed to investigate the pathogenesis and potential therapeutic targets of MS and to define target genes of matrine, a quinolizidine alkaloid component derived from the root of Sophorae flavescens that effectively suppressed experimental autoimmune encephalomyelitis (EAE), an animal model of MS. To this end, the GSE108000 gene data set in the Gene Expression Omnibus Database, which included 7 chronic active MS lesions and 10 control samples of white matter, was analyzed for differentially expressed genes (DEGs). X cell was used to analyze the microenvironmental differences in brain tissue samples of MS patients, including 64 types of immune cells and stromal cells. The biological functions and enriched signaling pathways of DEGs were analyzed by multiple approaches, including GO, KEGG, GSEA, and GSVA. The results by X cell showed significantly increased numbers of immune cell populations in the MS lesions, with decreased erythrocytes, megakaryocytes, adipocytes, keratinocytes, endothelial cells, Th1 cells and Tregs. In GSE108000, there were 637 DEGs, including 428 up-regulated and 209 down-regulated genes. Potential target genes of matrine were then predicted by the network pharmacology method of Traditional Chinese medicine, and 12 key genes were obtained by cross analysis of the target genes of matrine and DEGs in MS lesions. Finally, we confirmed by RT-PCR the predicted expression of these genes in brain tissues of matrine-treated EAE mice. Among these genes, 2 were significantly downregulated and 6 upregulated by matrine treatment, and the significance of this gene regulation was further investigated. In conclusion, our study defined several possible matrine target genes, which can be further elucidated as mechanism(s) of matrine action, and novel targets in the treatment of MS.


Assuntos
Alcaloides/farmacologia , Encéfalo/patologia , Encefalomielite Autoimune Experimental/patologia , Esclerose Múltipla/patologia , Quinolizinas/farmacologia , Transcriptoma/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Biologia Computacional/métodos , Encefalomielite Autoimune Experimental/imunologia , Perfilação da Expressão Gênica/métodos , Humanos , Camundongos , Esclerose Múltipla/imunologia
12.
Oncol Rep ; 45(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33786627

RESUMO

Ovarian cancer displays the highest mortality rate among all types of gynecological cancer worldwide. The survival of patients with ovarian cancer remains poor due to poor responses to anticancer treatments. The present study aimed to investigate the therapeutic effects and potential mechanism underlying matrine in ovarian cancer tissues, ovarian cancer cells and a CAOV­3­derived tumor­bearing mouse model. MTT, migration, invasion, flow cytometry, immunofluorescence and immunohistochemistry assays were performed to assess the inhibitory effects of matrine on ovarian cancer. A xenograft ovarian cancer mouse model was established and treated with matrine or PBS. The results demonstrated that compared with the control group, matrine significantly induced ovarian cancer cell apoptosis by upregulating caspase­8 and Fas cell surface death receptor (Fas) expression levels, and downregulating Bcl­2 and Bcl­xl expression levels. Moreover, compared with the control group, matrine significantly inhibited ovarian cancer cell viability, migration and invasion by downregulating metastasis associated protein­1, fibronectin, angiotensin II type 2 receptor-interacting protein 3a and H high mobility group AT­hook 2 expression levels. Compared with the control group, matrine significantly increased p38MAPK, phosphorylated (p)ERK/ERK and pJNK/JNK expression levels in ovarian cancer cells. p38MAPK knockdown significantly downregulated p38MAPK, pERK/ERK and pJNK/JNK expression levels compared with the control group, which significantly promoted ovarian cancer cell viability, migration and invasion. In vivo experiments demonstrated that compared with the control group, matrine significantly suppressed tumor growth by markedly upregulating p38MAPK, ERK and JNK expression levels. The immunohistochemistry results demonstrated that caspase­8 and Fas expression levels were notably increased, whereas Bcl­2 and Bcl­xl expression levels were obviously decreased in matrine­treated tumors compared with PBS­treated tumors. In conclusion, the present study demonstrated that matrine inhibited ovarian cancer cell viability, migration and invasion, but induced cell apoptosis, suggesting that matrine may serve as a promising anticancer agent for the treatment of ovarian cancer.


Assuntos
Alcaloides/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Quinolizinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Alcaloides/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Neoplasias Ovarianas/patologia , Quinolizinas/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
J Nat Med ; 75(3): 682-687, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33656740

RESUMO

Five matrine-type alkaloids (1‒5) including two new compounds (1 and 3) and a new natural product (2) were isolated from the roots of Sophora tonkinesis. Their structures were identified by extensive spectroscopic analysis (UV, IR, HRESIMS and NMR). The absolute configurations of 2 and 3 were determined by X-ray diffraction. Compounds 1‒5 were evaluated their activity against inflammatory cytokines TNF-α and IL-6 levels on LPS-induced RAW 264.7 macrophages, and compound 1 showed the most significant activity, potent than that of matrine, the representative ingredient from Sophora plants.


Assuntos
Alcaloides/farmacologia , Anti-Inflamatórios/química , Quinolizinas/farmacologia , Sophora/química , Alcaloides/química , Animais , China , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , Raízes de Plantas/química , Células RAW 264.7
14.
Drug Deliv ; 28(1): 325-342, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33517789

RESUMO

The aim of the present study was to investigate the pharmacological mechanism of matrine in treatment of COVID-19 combined with liver injury. Potential targets related to matrine, COVID-19 and liver injury were identified from several databases. We constructed PPI network and screened the core targets according to the degree value. Then, GO and KEGG enrichment were carried out. Molecular docking technology was used to verify the affinity between matrine and the crystal structure of core target protein. Finally, real-time RT-PCR was used to detect the effects of matrine on hub gene expression in liver tissue of liver injury mice and lung tissue of lung injury mice to further confirm the results of network pharmacological analysis. The results show that six core targets including AKT1, TP53, TNF, IL6, BCL2L1 and ATM were identified. The potential therapeutic mechanism of matrine on COVID-19 combined with liver injury is closely related to regulate antiviral process, improve immune system and regulate the level of inflammatory factors. Molecular docking showed that matrine could spontaneously bind to the receptor protein and had strong binding force. Real-time RT-PCR demonstrated that matrine could significantly reduce the expression of AKT1, TP53, TNF, IL6 and ATM in mice with liver injury or lung injury (P < 0.05), and increase the expression of BCL2L1 to a certain extent (P > 0.05). Our results indicate that matrine can achieve simultaneous intervention of COVID-19 combined with liver injury by multi-dimensional pharmacological mechanism.


Assuntos
Alcaloides/farmacologia , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Simulação de Acoplamento Molecular/métodos , Quinolizinas/farmacologia , Alcaloides/administração & dosagem , Animais , Antivirais/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Relação Dose-Resposta a Droga , Humanos , Lipopolissacarídeos/farmacologia , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinolizinas/administração & dosagem , Reação em Cadeia da Polimerase em Tempo Real , SARS-CoV-2 , Transdução de Sinais/efeitos dos fármacos
15.
Vet J ; 269: 105610, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33593492

RESUMO

Alpha-2-adrenoceptor agonists are sedatives that can cause fluctuations in serum insulin and blood glucose (BG) concentrations in horses. The objectives of this study were to investigate the effects of detomidine and vatinoxan on BG, insulin, and glucagon concentrations in horses with and without insulin dysregulation (ID). In a blinded cross-over design, eight horses with ID and eight horses without ID were assigned to each of four treatments: detomidine (0.02 mg/kg; DET), vatinoxan (0.2 mg/kg; VAT), detomidine + vatinoxan (DET + VAT), and saline control (SAL). Blood samples were taken at 0, 1, 2, 4, 6, and 8 h. Change from baseline was used as the response in modelling, and the differences between treatments were evaluated with repeated measures analysis of covariance. P values ≤0.05 were considered significant. Comparing DET vs. SAL and DET vs. DET + VAT, insulin was higher at 2 h in the non-ID group and 2 and 4 h in the ID group. There was no difference in insulin between SAL and DET + VAT or VAT. Comparing DET vs. SAL, BG was higher at 1 and 2 h then was lower at 4 h in both ID and non-ID groups. At 1 h in both groups, BG after DET + VAT was lower than after DET but higher than after SAL. Comparing DET vs. SAL, glucagon was lower at 1 h in the ID group and 1 and 2 h in the non-ID group. Vatinoxan was effective in preventing detomidine-induced hyperglycaemia as well as the subsequent insulin increase in horses with ID.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Glicemia/análise , Glucagon/sangue , Cavalos/sangue , Insulina/sangue , Animais , Interações Medicamentosas , Feminino , Hipnóticos e Sedativos/farmacologia , Imidazóis/farmacologia , Resistência à Insulina/fisiologia , Masculino , Quinolizinas/farmacologia
16.
Phytomedicine ; 84: 153505, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33626426

RESUMO

BACKGROUND: Ischemic stroke (IS) is a major neurological condition associated with extremely high morbidity and mortality worldwide. Oxymatrine (OMT), a quinolizidine alkaloid extracted from the root of Sophora flavescens, has neuroprotective properties and protects against IS. However, whether its protective effect involves alterations in the integrity of the blood-brain barrier (BBB) is unknown. PURPOSE: Here, we used in vivo and in vitro models of IS to evaluate the protective effects of OMT and to establish whether its effects are mediated via the modulation of the BBB function. METHODS: We assessed the effects of OMT by using neurological function scores, triphenyltetrazolium chloride staining, Nissl staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling. RESULTS: OMT significantly prevented cellular damage, improved neurological function, and reduced BBB permeability in a mouse model of cerebral ischemia-reperfusion. Additionally, OMT protected the function of the tight junctions of bEend.3 cells against the consequences of oxygen-glucose deprivation. Furthermore, intracranial lentivirus injection of short hairpin RNA targeting Cav1 decreased caveolin-1 expression and inhibited the neuroprotective effects of OMT. CONCLUSIONS: OMT attenuated ischemia-reperfusion injury-induced damage to the BBB, and this neuroprotective action was at least partially dependent on the expression levels of CAV1 and MMP9 proteins. Therefore, OMT may offer effective protection against BBB injury induced by ischemia-reperfusion episodes.


Assuntos
Alcaloides/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Caveolina 1/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Fármacos Neuroprotetores/farmacologia , Quinolizinas/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Isquemia Encefálica/patologia , Isquemia Encefálica/prevenção & controle , Caveolina 1/genética , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Permeabilidade , Sophora/química
17.
Phytomedicine ; 84: 153507, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33636577

RESUMO

BACKGROUND: Matrine (Mat), a bitter tastes compounds of derived from leguminosae such as Sophora flavescens and S. subprostrata, commonly used to improve obesity and diabetes. PURPOSE: Our study to demonstrate bitter substances can stimulate the Bitter taste receptors (TAS2Rs) or Calcium-sensing receptor (CaSR) to stimulate the secretion of GLP-1 to promote blood glucose regulation. METHODS: The diabetic mice and intestinal secretory cell model were established to evaluate the Mat on glucose metabolism, intestinal insulin secretion and GLP-1 secretion related substances. To clarify the mechanism of Mat in regulating GLP-1 secretion by immunofluorescence, calcium labeling, siRNA, and molecular docking. RESULTS: The results showed that Mat could significantly improve glucose metabolism and increased insulin and GLP-1 secretion in diabetic mice and increased trisphosphate inositol (IP3) levels by affecting the expression of phospholipase C ß2 (PLCß2) and promote an increase in intracellular Ca2+ levels in STC-1 cells to subsequently stimulate the secretion of GLP-1. Knockdown of the bitter taste receptors mTas2r108, mTas2r137, and mTas2r138 in STC-1 cells by siRNA did could not affect the role of Mat in regulating GLP-1. However, the secretion of GLP-1 by Mat could be significantly inhibited by administration of a CaSR inhibitor or siRNA CaSR. Molecular docking analysis showed that Mat could embed CaSR protein and bind to the original ligand of the egg white at the same amino acid site to play the role of an agonist. CONCLUSION: Matrine is a typical bitter alkaloid could be used as an agonist of CaSR to stimulate the secretion of GLP-1 in the intestine, and it may be used as a potential drug for diabetes treatment.


Assuntos
Alcaloides/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Intestinos/efeitos dos fármacos , Quinolizinas/farmacologia , Receptores de Detecção de Cálcio/agonistas , Alcaloides/química , Alcaloides/metabolismo , Animais , Linhagem Celular , Diabetes Mellitus Experimental/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Resistência à Insulina/fisiologia , Intestinos/citologia , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Fosfolipase C beta/metabolismo , Quinolizinas/química , Quinolizinas/metabolismo , Receptores de Detecção de Cálcio/química , Receptores de Detecção de Cálcio/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo
18.
Chem Biodivers ; 18(4): e2000979, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33605042

RESUMO

In this article, we designed and synthesized two series of matrine analogs with ring-opening in the lactam portion of the molecule. Our in vitro cytotoxicity study showed that analog N-(3-bromophenyl)-4-[(1R,3aS,10aR,10bS)-decahydro-1H,4H-pyrido[3,2,1-ij][1,6]naphthyridin-1-yl]butanamide (B11) with a meta-bromide on the phenyl ring displayed the best antiproliferative activity. Moreover, B11 induced cell cycle arrest in G1 phase and cell apoptosis in a dose-dependent manner in A549 cells. Molecular modeling revealed that B11 achieved a higher docking score compared to its precursor tert-butyl (1R,3aS,10aR,10bS)-1-[4-(3-bromoanilino)-4-oxobutyl]octahydro-1H,4H-pyrido[3,2,1-ij][1,6]naphthyridine-2(3H)-carboxylate (A11, an analog of B11 with a Boc group) and parent compound matrine, possibly because B11 formed a hydrogen bond with SER91 and a halogen bond with GLN320 on the binding site of annexin A2. Overall, we discovered the potential anticancer lead compound B11, which can be used for further study both in vitro and in vivo.


Assuntos
Alcaloides/farmacologia , Amidas/farmacologia , Antineoplásicos/farmacologia , Quinolizinas/farmacologia , Alcaloides/síntese química , Alcaloides/química , Amidas/síntese química , Amidas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinolizinas/síntese química , Quinolizinas/química
19.
Eur J Pharmacol ; 895: 173869, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33454375

RESUMO

The purpose of this study was to investigate the analgesic interaction between matrine and paracetamol in an acetic acid-induced writhing model in mice. Fifty percent effective dose (ED50) values of the individual drugs were determined, and the different proportions of matrine and paracetamol were assayed using the isobolographic method. Our study demonstrated that both of matrine and paracetamol dose-dependently inhibited the writhing response evoked by acetic acid, and the ED50 values and their 95% confidence intervals against these tonic pain were 21.10 (17.86-24.92) mg/kg and 61.30 (50.71-74.10) mg/kg for matrine and paracetamol, respectively. At the fixed ratios of 1:1, 1:3 and 3:1, the experimental ED50 values of matrine and paracetamol combinations and their 95% confidence intervals were 10.52 (5.14-21.55) mg/kg, 9.13 (4.46-18.70) mg/kg and 4.98 (4.17-5.95) mg/kg, respectively, their theoretical ED50 values and 95% confidence intervals were 41.20 (36.31-46.74) mg/kg, 51.25 (44.19-59.44) mg/kg and 31.15 (27.25-35.60) mg/kg, and the experimental ED50 values of matrine and paracetamol combination were significantly lower than their calculated theoretical ED50 values (all P < 0.01), as revealed by isobolographic analysis. Furthermore, the experimental regression line was also significantly different from the calculated additive equal-effect line over the range of the tested doses (all P < 0.01). Our results suggest that the combination of matrine with paracetamol exerts analgesic synergistic interactions in a mouse acetic acid-induced writhing model, thereby offering a possible therapeutic alternative for the clinical management of inflammatory pain.


Assuntos
Acetaminofen/farmacologia , Alcaloides/farmacologia , Analgésicos/farmacologia , Comportamento Animal/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Dor/prevenção & controle , Quinolizinas/farmacologia , Ácido Acético , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Masculino , Camundongos , Dor/induzido quimicamente , Dor/fisiopatologia , Dor/psicologia
20.
J Neuroimmunol ; 352: 577480, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33493985

RESUMO

The inflammatory mediator high-mobility group box 1 (HMGB1)-induced signaling pathway has been shown to play an important role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Matrine (MAT), a quinolizidine alkaloid component derived from the root of Sophorae flavescens, has the capacity to effectively suppress EAE. However, the impact of MAT treatment on HMGB1-induced signaling is not known. In the present study, we show that MAT treatment alleviated disease severity of ongoing EAE, reduced inflammatory infiltration and demyelination, and reduced the production of inflammatory factors including TNF-α, IL-6, and IL-1ß in the CNS. Moreover, MAT administration significantly reduced the protein and RNA expression of HMGB1 and TLR4 in the spinal cord, particularly in astrocytes and microglia/infiltrating macrophages. The expression of MyD88 and TRAF6, and the phosphorylation of NF-κB p65, was also down-regulated after MAT treatment. In contrast, the level of IκB-α, an inhibitory molecule for NF-κB activation, was significantly increased. Furthermore, the direct inhibitory effect of MAT on HMGB1/TLR4/NF-κB signaling in macrophages was further confirmed in vitro. Taken together, these findings demonstrate that MAT treatment alleviated CNS inflammatory demyelination and activation of astrocytes and microglia/macrophages in EAE rats, and that the mechanism underlying these effects may be closely related to modulation of HMGB1/TLR4/NF-κB signaling pathway.


Assuntos
Alcaloides/farmacologia , Encefalomielite Autoimune Experimental/metabolismo , Quinolizinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Animais , Encefalomielite Autoimune Experimental/patologia , Feminino , Proteína HMGB1/efeitos dos fármacos , Proteína HMGB1/metabolismo , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Ratos , Ratos Wistar , Medula Espinal/patologia , Receptor 4 Toll-Like/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo
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