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1.
Phytochemistry ; 200: 113217, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35504329

RESUMO

Berberine alkaloids belong to the class of isoquinoline alkaloids that have been shown to possess anticancer potential, berberine exhibits inhibitory effects on breast cancer development. However, the exact mechanisms of action for anti-breast carcinoma of the alkaloids, including epiberberine, berberrubine and dihydroberberine are still unclear. MTT assay, colony formation, wound healing and transwell invasion assays detected these alkaloids suppressed proliferation, migration and invasion of breast cancer cells. Hoechst and Annexin V-FITC/PI staining were used to analyze the apoptosis of breast cancer cells. Western blotting investigated the changes noted in the expression levels of the key proteins involved in the Wnt/ß-catenin signaling pathway and epithelial to mesenchymal transition (EMT). The results showed that inhibited the proliferation of breast cancer cells. Berberine alkaloids inhibited the cell cycle at G2/M phase in MCF-7 cells, but in MDA-MB-231 cells berberine alkaloids arrested the cell cycle in G0/G1 and G2/M phases. By decreasing ß-catenin expression, increasing GSK-3ß expression and decreasing N-cadherin expression, increasing E-cadherin expression, which proved that epiberberine, berberrubine and dihydroberberine inhibited of metastasis of breast cancer cells through Wnt signaling pathway and reversed EMT except berberine. Furthermore, berberine alkaloids exert their anti-breast cancer effects through the synergistic action of intrinsic and extrinsic pathways of apoptosis. These findings highlight the different effects of different berberine alkaloids on breast cancer cells and confirm that berberine alkaloids may be potentially used in the treatment of breast cancer.


Assuntos
Alcaloides de Berberina , Berberina , Neoplasias da Mama , Via de Sinalização Wnt , Berberina/farmacologia , Alcaloides de Berberina/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo
2.
Int Immunopharmacol ; 104: 108468, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35066343

RESUMO

BACKGROUND: Previous studies have substantiated that M2-activated tumor-associated macrophages (M2-TAMs) are involved in multiple malignancies. Presently, we probe the impact and related mechanisms of 13-methyl-palmatrubine (13MP), the Corydalis yanhusuo extract, on M2-TAM-mediated non-small cell lung cancer (NSCLC) development. METHODS: IL-4 and IL-13 were adopted to induce M2-TAMs. The polarization state of TAMs was evaluated by quantitative reverse transcription PCR (qRT-PCR), Western blot (WB) and cellular immunofluorescence. NSCLC cells (A549 and NCL-H1975) were co-cultured with the conditioned medium (CM) of M2-TAMs. Followed by 13MP treatment, cell viability, proliferation, invasion, epithelial-mesenchymal transition (EMT), and in-vivo growth of NSCLC cells were determined. Additionally, human umbilical vein endothelial cells (HUVECs) were co-cultured with the CM of M2-TAMs. The tube formation assay was made to test the tube formation capacity of HUVECs, and the expression of MMP3, MMP9, and VEGF was assessed by WB in the co-culture model. Mechanistically, WB was performed to validate the expression of the PI3K/AKT and JAK/STAT3 pathways in NSCLC cells (A549 and NCL-H1975) as well as in endothelial cell lines co-cultured with M2-TAMs. RESULTS: 13MP inhibited the proliferation, invasion, EMT, growth and enhanced apoptosis of NSCLC cells. 13MP dose-dependently boosted the polarization of TAM from M2 to M1 state. M2-TAMs enhanced the malignant behaviors of NSCLC cells, whereas 13MP hindered M2-TAM-mediated NSCLC cell proliferation and invasion. Meanwhile, 13MP weakened the M2-TAM-mediated angiogenesis. Moreover, 13MP inactivated the PI3K/AKT and JAK/STAT3 signaling in A549 cells, NCL-H1975 cells and HUVECs. CONCLUSION: 13MP suppresses TAM-mediated NSCLC progression via transforming the polarization of TAM from M2 to M1.


Assuntos
Antineoplásicos/uso terapêutico , Alcaloides de Berberina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Alcaloides de Berberina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Citocinas/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia
3.
Biomed Pharmacother ; 147: 112645, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35051862

RESUMO

Plants are a rich source for bioactive compounds. However, plant extracts can harbor a mixture of bioactive molecules that promote divergent phenotypes and potentially have confounding effects in bioassays. Even with further purification and identification, target deconvolution can be challenging. Corynoline and acetylcorynoline, are phytochemicals that were previously isolated through a screen for compounds able to induce mitotic arrest and polyploidy in oncogene expressing retinal pigment epithelial (RPE) cells. Here, we shed light on the mechanism by which these phytochemicals can attack human cancer cells. Mitotic arrest was coincident to the induction of centrosome amplification and declustering, causing multi-polar spindle formation. Corynoline was demonstrated to have true centrosome declustering activity in a model where A549 cells were chemically induced to have more than a regular complement of centrosomes. Corynoline could inhibit the centrosome clustering required for pseudo-bipolar spindle formation in these cells. The activity of AURKB, but not AURKA or polo-like kinase 4, was diminished by corynoline. It only partially inhibited AURKB, so it may be a partial antagonist or corynoline may work upstream on an unknown regulator of AURKB activity or localization. Nonetheless, corynoline and acetylcorynoline inhibited the viability of a variety of human cancer derived cell lines. These phytochemicals could serve as prototypes for a next-generation analog with improved potency, selectivity or in vivo bioavailability. Such an analog could be useful as a non-toxic component of combination therapies where inhibiting the chromosomal passenger protein complex is desired.


Assuntos
Aurora Quinase B/efeitos dos fármacos , Alcaloides de Berberina/farmacologia , Mitose/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Poliploidia , Células A549 , Apoptose/efeitos dos fármacos , Aurora Quinase A/efeitos dos fármacos , Linhagem Celular Tumoral , Centrossomo/efeitos dos fármacos , Humanos
4.
J Nat Prod ; 85(1): 215-224, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-34910498

RESUMO

During a research program to identify new cholinesterase inhibitors of natural origin, two new 7,8-didehydroprotoberberine alkaloids (1 and 2) and nine known compounds (3-11) were isolated from the capsules of the common ornamental poppy, Papaver setiferum (previously P. pseudo-orientale). Despite their reported instability, the 7,8-didehydroprotoberberines isolated herein appeared relatively stable, particularly as their trifluoroacetic acid salts. The spatial distributions of the isolated alkaloids were also analyzed using desorption electrospray ionization imaging mass spectrometry. The alkaloids were localized predominantly within the walls and vascular bundles of the capsules, with the highest relative abundances occurring in the lower half of the capsules toward the peduncle. The relative abundances of the alkaloids were also compared across plant development stages. Although most alkaloids did not show clear patterns in their concentration across development stages, the concentration of suspected oxidation products clearly spiked upon plant death. Finally, all isolated natural products were screened for inhibitory activities against a panel of cholinesterases, from both human and animal sources. These studies identified several competitive inhibitors of cholinesterases with potency in the low micromolar range (1-4, 6, 7), offering new lead compounds for the development of cholinesterase inhibitory drugs.


Assuntos
Alcaloides de Berberina/farmacologia , Inibidores da Colinesterase/farmacologia , Papaver/química , Animais , Alcaloides de Berberina/química , Humanos , Espectrometria de Massas por Ionização por Electrospray
5.
Int J Mol Sci ; 22(23)2021 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-34884773

RESUMO

STAT3 is a transcription factor that regulates various cellular processes with oncogenic potential, thereby promoting tumorigenesis when activated uncontrolled. STAT3 activation is mediated by its tyrosine phosphorylation, triggering dimerization and nuclear translocation. STAT3 also contains a serine phosphorylation site, with a postulated regulatory role in STAT3 activation and G2/M transition. Interleukin-6, a major activator of STAT3, is present in elevated concentrations in uveal melanomas, suggesting contribution of dysregulated STAT3 activation to their pathogenesis. Here, we studied the impact of chelidonine on STAT3 signaling in human uveal melanoma cells. Chelidonine, an alkaloid isolated from Chelidonium majus, disrupts microtubules, causes mitotic arrest and provokes cell death in numerous tumor cells. According to our flow cytometry and confocal microscopy data, chelidonine abrogated IL-6-induced activation and nuclear translocation, but amplified constitutive serine phosphorylation of STAT3. Both effects were restricted to a fraction of cells only, in an all-or-none fashion. A partial overlap could be observed between the affected subpopulations; however, no direct connection could be proven. This study is the first proof on a cell-by-cell basis for the opposing effects of a microtubule-targeting agent on the two types of STAT3 phosphorylation.


Assuntos
Benzofenantridinas/farmacologia , Alcaloides de Berberina/farmacologia , Melanoma/patologia , Fator de Transcrição STAT3/metabolismo , Neoplasias Uveais/patologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Interleucina-6/metabolismo , Microtúbulos/metabolismo , Fosforilação/efeitos dos fármacos , Serina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tirosina/metabolismo
6.
Molecules ; 26(23)2021 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-34885971

RESUMO

Rhizoma Coptidis (RC) is a widely used traditional Chinese medicine. Although modern research has found that some alkaloids from RC are the pharmacologically active constituents, the differences in their biological effects are not completely clear. This study analyzed the differences in the typical alkaloids in RC at a systematic level and provided comprehensive information on the pharmaceutical mechanisms of the different alkaloids. The ethanol RC extract (RCE) was characterized using HPLC assay. HepG2, 3T3-L1, and RAW264.7 cells were used to detect the cytotoxicity of alkaloids. Transcriptome analyses were performed to elucidate the cellular pathways affected by RCE and alkaloids. HPLC analysis revealed that the typical alkaloids of RCE were berberine, coptisine, and palmatine. Coptisine and berberine displayed a stronger inhibitory effect on cell proliferation than palmatine. The overlapping ratios of differentially expressed genes between RCE and berberine, coptisine, and palmatine were 70.8%, 52.6%, and 42.1%, respectively. Pathway clustering analysis indicated that berberine and coptisine possessed a certain similarity to RCE, and both compounds affected the cell cycle pathway; moreover, some pathways were uniquely enriched by berberine or coptisine. Berberine and coptisine had different regulatory effects on genes involved in lipid metabolism. These results provide comprehensive information on the pharmaceutical mechanisms of the different RC alkaloids and insights into their better combinatory use for the treatment of diseases.


Assuntos
Alcaloides de Berberina/farmacologia , Berberina/análogos & derivados , Coptis/química , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Rizoma/química , Células 3T3-L1 , Animais , Berberina/análise , Berberina/farmacologia , Alcaloides de Berberina/análise , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Camundongos , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética
8.
Molecules ; 26(20)2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34684834

RESUMO

Palmatine (PLT) is a natural isoquinoline alkaloid that belongs to the class of protoberberines and exhibits a wide spectrum of pharmacological and biological properties, including anti-cancer activity. The aim of our study was to isolate PLT from the roots of Berberis cretica and investigate its cytotoxic and anti-proliferative effects in vitro alone and in combination with doxorubicine (DOX) using human ER+/HER2- breast cancer cell lines. The alkaloid was purified by column chromatography filled with silica gel NP and Sephadex LH-20 resin developed in the mixture of methanol: water (50:50 v/v) that provided high-purity alkaloid for bioactivity studies. The purity of the alkaloid was confirmed by high resolution mass measurement and MS/MS fragmentation analysis in the HPLC-ESI-QTOF-MS/MS-based analysis. It was found that PLT treatment inhibited the viability and proliferation of breast cancer cells in a dose-dependent manner as demonstrated by MTT and BrdU assays. PLT showed a quite similar growth inhibition on breast cancer cells with IC50 values ranging from 5.126 to 5.805 µg/mL. In contrast, growth of normal human breast epithelial cells was not affected by PLT. The growth inhibitory activity of PLT was related to the induction of apoptosis, as determined by Annexin V/PI staining. Moreover, PLT sensitized breast cancer cells to DOX. Isobolographic analysis revealed synergistic and additive interactions between studied agents. Our studies suggest that PLT can be a potential candidate agent for preventing and treating breast cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Alcaloides de Berberina/farmacologia , Neoplasias da Mama/tratamento farmacológico , Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Apoptose/efeitos dos fármacos , Alcaloides de Berberina/administração & dosagem , Berberis/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Sinergismo Farmacológico , Feminino , Humanos , Células MCF-7 , Fitoterapia , Raízes de Plantas/química , Plantas Medicinais/química , Receptores de Estrogênio/metabolismo
9.
Mol Pain ; 17: 17448069211042117, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34505815

RESUMO

BACKGROUND: Pain is an unpleasant sensory experience that usually plays a protective role. Inflammatory pain is often severe and stubborn, which has a great impact on the quality of life of patients. However, there has been no breakthrough in the treatment strategy and mechanism of inflammatory pain. METHODS: This study investigated the analgesic effect of tetrahydropalmatine (THP) in rats injected with complete Freund's adjuvant (CFA)-induced inflammatory pain. Allodynia and gait analysis of rats were used to evaluate the analgesic effect at different time points before and after operation. THP (2.5, 5, and 10 mg/kg) was administered intraperitoneally once daily for 7 days post Day 3. The expression levels of TNF-α and IL-1ß in the spinal cord were measured by enzyme-linked immunosorbent assay. The activation of astrocytes and microglial cells in the spinal cord was tested by western blot before and after THP treatment. The apoptosis of glial cells was tested by flow cytometry after treatment with THP in the primary cultured glial cell model. RESULTS: CFA treatment induced significant allodynia and caused abnormal gait in rats. Administration of THP at 10 mg/kg significantly alleviated CFA-induced inflammatory pain behaviors. Moreover, CFA-induced activation of glial cells and the increased levels of TNF-α and IL-1ß were inhibited by THP administration. In addition, THP promotes apoptosis in primary cultured glial cells. This study suggests the possible clinical utility of THP in the treatment of inflammatory pain. CONCLUSION: THP plays an analgesic role by inhibiting the activation of glial cells and promoting apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Alcaloides de Berberina/farmacologia , Inflamação/tratamento farmacológico , Neuroglia/efeitos dos fármacos , Dor/tratamento farmacológico , Animais , Astrócitos/metabolismo , Modelos Animais de Doenças , Adjuvante de Freund/efeitos adversos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Masculino , Microglia/efeitos dos fármacos , Neuroglia/metabolismo , Dor/metabolismo , Ratos Sprague-Dawley , Medula Espinal/metabolismo
10.
Int Immunopharmacol ; 100: 108107, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34482265

RESUMO

Activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome plays a crucial role in the inflammatory responses of monosodium urate (MSU) crystal-induced gouty arthritis. Therefore, the molecular basis of NLRP3 inflammasome is very valuable in developing potential therapeutic drugs for gout. Tetrahydropalmatine (THP), the main active component of the traditional Chinese medicinal herb Corydalis yanhusuo, has shown prominent anti-inflammatory and analgesic activities, but to date, these effects have not been investigated exhaustively on gout. This study indicated that THP attenuated pain and swelling in an MSU-induced acute gout model by decreasing pro-inflammatory cytokine production and inflammatory cell infiltration. THP exerted its actions by suppressing NLRP3 inflammasome activation and subsequent formation of caspase-1. Furthermore, results showed that THP alleviated MSU-induced reactive oxygen species (ROS) generation, upstream of NLRP3 inflammasome activation, by an increase in the activities of antioxidant enzymes both in vitro and in vivo. In conclusion, our study suggests that THP suppressed ROS-mediated NLRP3 inflammasome activation in MSU-induced inflammatory responses, which highlights its therapeutic potential in gouty arthritis.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Artrite Gotosa/prevenção & controle , Alcaloides de Berberina/farmacologia , Inflamassomos/metabolismo , Articulações/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Analgésicos/farmacologia , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/imunologia , Artrite Gotosa/metabolismo , Caspase 1/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Articulações/imunologia , Articulações/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Células RAW 264.7 , Transdução de Sinais , Ácido Úrico
11.
Oxid Med Cell Longev ; 2021: 9966223, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34567416

RESUMO

Palmatine is a naturally occurring isoquinoline alkaloid that has been reported to display neuroprotective effects against amyloid-ß- (Aß-) induced neurotoxicity. However, the mechanisms underlying the neuroprotective activities of palmatine remain poorly characterized in vivo. We employed transgenic Caenorhabditis elegans models containing human Aß 1-42 to investigate the effects and possible mechanisms of palmatine-mediated neuroprotection. Treatment with palmatine significantly delayed the paralytic process and reduced the elevated reactive oxygen species levels in Aß-transgenic C. elegans. In addition, it increased oxidative stress resistance without affecting the lifespan of wild-type C. elegans. Pathway analysis suggested that the differentially expressed genes were related mainly to aging, detoxification, and lipid metabolism. Real-time PCR indicated that resistance-related genes such as sod-3 and shsp were significantly upregulated, while the lipid metabolism-related gene fat-5 was downregulated. Further studies demonstrated that the inhibitory effects of palmatine on Aß toxicity were attributable to the free radical-scavenging capacity and that the upregulated expression of resistance-related genes, especially shsp, whose expression was regulated by HSF-1, played crucial roles in protecting cells from Aß-induced toxicity. The research showed that there were significantly fewer Aß deposits in transgenic CL2006 nematodes treated with palmatine than in control nematodes. In addition, our study found that Aß-induced toxicity was accompanied by dysregulation of lipid metabolism, leading to excessive fat accumulation in Aß-transgenic CL4176 nematodes. The alleviation of lipid disorder by palmatine should be attributed not only to the reduction in fat synthesis but also to the inhibition of Aß aggregation and toxicity, which jointly maintained metabolic homeostasis. This study provides new insights into the in vivo neuroprotective effects of palmatine against Aß aggregation and toxicity and provides valuable targets for the prevention and treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/toxicidade , Alcaloides de Berberina/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Proteínas de Choque Térmico Pequenas/metabolismo , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Animais Geneticamente Modificados , Antioxidantes/farmacologia , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Choque Térmico Pequenas/genética , Humanos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo
12.
Drug Des Devel Ther ; 15: 4043-4052, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34588765

RESUMO

INTRODUCTION: Synergy is defined as an interaction of some substances that cooperate to give rise to the combined effect greater than the sum of their individual effects. It is a natural strategy that has evolved by nature to more efficacy with low cost. METHODS: This study is designed to evaluate the chemopreventive effect of a combined drug sample which is prepared by mixing an equal portion of stigmasterol and palmatine isolated from Azadirachta indica and Tinospora cordifolia respectively at a concentration of 100 mg/kg and 200 mg/kg body weight during the whole concentration. RESULTS: At the end of the study, it was found that this combined drug sample decreased the number of tumors and their size. This drug significantly reduced the serum level of glutamate pyruvate transaminase, alkaline phosphatase, glutamate oxalate transaminase, and bilirubin and enhanced the level of oxidative enzyme level of glutathione, superoxide dismutase, and catalase, and inhibit the level of lipid peroxides. DISCUSSION: The result suggests that combined drug samples exhibit a chemopreventive effect which is better than the effect of individual drugs (stigmasterol and palmatine).


Assuntos
Azadirachta/química , Alcaloides de Berberina/farmacologia , Estigmasterol/farmacologia , Tinospora/química , Animais , Anticarcinógenos/administração & dosagem , Anticarcinógenos/isolamento & purificação , Anticarcinógenos/farmacologia , Alcaloides de Berberina/administração & dosagem , Alcaloides de Berberina/isolamento & purificação , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Sinergismo Farmacológico , Feminino , Masculino , Camundongos , Estigmasterol/administração & dosagem , Estigmasterol/isolamento & purificação
13.
Org Lett ; 23(16): 6342-6347, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34355910

RESUMO

Tetrahydroprotoberberine and protoberberine alkaloids are a group of biologically active natural products with complex molecular scaffolds. Isolation from plants is challenging and stereoselective synthetic routes, particularly of methylated compounds are limited, reducing the potential use of these compounds. In this work, we describe chemoenzymatic cascades toward various 13-methyl-tetrahydroprotoberberbine scaffolds using a stereoselective Pictet-Spenglerase, regioselective catechol O-methyltransferases and selective chemical Pictet-Spengler reactions. All reactions could be performed sequentially, without the workup or purification of any synthetic intermediates. Moreover, the naturally occurring alkaloids have the (+)-configuration and importantly here, a strategy to the (-)-isomers was developed. A methyl group at C-8 was also introduced with some stereocontrol, influenced by the stereochemistry at C-13. Furthermore, a single step reaction was found to convert tetrahydroprotoberberine alkaloids into the analogous protoberberine scaffold, avoiding the use of harsh oxidizing conditions or a selective oxidase. This work provides facile, selective routes toward novel analogues of bioactive alkaloids.


Assuntos
Alcaloides/química , Alcaloides de Berberina/farmacologia , Alcaloides/isolamento & purificação , Alcaloides de Berberina/química , Alcaloides de Berberina/isolamento & purificação , Produtos Biológicos , Estrutura Molecular
14.
Phytomedicine ; 91: 153702, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34419734

RESUMO

BACKGROUND: Migraine is the third most common disease worldwide, leading to severely decreased quality of life for the patients. In spite of great efforts endeavored in pharmacological and nonpharmacological therapeutic strategies for treating migraine, the outcome is rather disappointing in terms of efficacy. Compelling evidence shows that the expression level of dopamine receptor D2 (DRD2) plays an essential role in progression of migraine. PURPOSE: To explore potential therapeutical possibilities, the attention was paid to Yuanhu Zhitong formula (YHZTF), which is a classical traditional Chinese medicine prescription frequently applied to relieve pain. The aim of this study was to identify the promising compounds derived from YHZTF with anti-migraine effects and investigate the underlying molecular mechanism. METHODS: The high-resolution mass spectrometry and molecular networking were performed for comprehensive chemical profiling of YHZTF. Network pharmacology was used to generate herbal-component-target-pathway network. Based on the pathway enrichment analysis, the active substances of anti-migraine and the potential molecular mechanism were further determined by performing animal experiments combined with molecular docking strategy. RESULTS: In total, 31 substances were identified in YHZTF, including alkaloids such as tetrahydropalmatine and protopine. The analysis of herbal-component-target-pathway network suggests that the alkaloid substances (e.g. tetrahydropalmatine and protopine) from YHZTF target dopamine receptors, thus can be linked to neuroactive ligand-receptor interaction pathways. In a nitroglycerin-induced migraine animal model, pretreatment with tetrahydropalmatine or protopine substantially lessened the aberrant migraine-like symptoms. The results of molecular docking analysis showed that tetrahydropalmatine and protopine had strong affinities to dopamine receptor D2 (DRD2). Using RT-qPCR, the investigators found that DRD2 was significantly down-regulated at the mRNA level in brain tissues of tetrahydropalmatine and protopine-treated group compared to the control group. CONCLUSION: Collectively, the results provide reliable evidence showing that the active substances tetrahydropalmatine and protopine from YHZTF lessens migraine symptoms in an in vivo mouse model suggestively via regulating expression of DRD2. These findings shed light on novel therapeutic strategies and targets to treat migraine using natural products.


Assuntos
Benzofenantridinas/farmacologia , Alcaloides de Berberina/farmacologia , Medicamentos de Ervas Chinesas , Transtornos de Enxaqueca , Receptores de Dopamina D2/metabolismo , Animais , Medicamentos de Ervas Chinesas/farmacologia , Camundongos , Transtornos de Enxaqueca/tratamento farmacológico , Simulação de Acoplamento Molecular
15.
J Nat Prod ; 84(8): 2312-2320, 2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34406008

RESUMO

To identify novel bioactive compounds, an image-based, cell culture screening of natural product extracts was conducted. Specifically, our screen was designed to identify phytochemicals that might phenocopy inhibition of the chromosomal passenger protein complex in eliciting mitotic and cytokinetic defects. A known alkaloid, scoulerine, was identified from the rhizomes of the plant Corydalis decumbens as being able to elicit a transient mitotic arrest followed by either apoptosis induction or polyploidy. In examining the mitotic abnormality further, we observed that scoulerine could elicit supernumerary centrosomes during mitosis, but not earlier in the cell cycle. The localization of NUMA1 at spindle poles was also inhibited, suggesting diminished potential for microtubule recruitment and spindle-pole focusing. Polyploid cells emerged subsequent to cytokinetic failure. The concentration required for scoulerine to elicit all its cell division phenotypes was similar, and an examination of related compounds highlighted the requirement for proper positioning of a hydroxyl and a methoxy group about an aromatic ring for activity. Mechanistically, scoulerine inhibited AURKB activity at concentrations that elicited supernumerary centrosomes and polyploidy. AURKA was only inhibited at higher concentrations, so AURKB inhibition is the likely mechanism by which scoulerine elicited division defects. AURKB inhibition was never complete, so scoulerine may be a suboptimal AURK inhibitor or work upstream of the chromosomal passenger protein complex to reduce AURKB activity. Scoulerine inhibited the viability of a variety of human cancer cell lines. Collectively, these findings uncover a previously unknown activity of scoulerine that could facilitate targeting human cancers. Scoulerine, or a next-generation analogue, may be useful as a nontoxic component of combination therapies where inhibiting the chromosomal passenger protein complex is desired.


Assuntos
Aurora Quinase A/antagonistas & inibidores , Aurora Quinase B/antagonistas & inibidores , Alcaloides de Berberina/farmacologia , Citocinese/efeitos dos fármacos , Mitose/efeitos dos fármacos , Alcaloides de Berberina/isolamento & purificação , Linhagem Celular , China , Corydalis/química , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Humanos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Rizoma/química
16.
J Ethnopharmacol ; 280: 114457, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34329712

RESUMO

ETHNOPHARMACOLOGY RELEVANCE: Pain often causes a series of abnormal changes in physiology and psychology, which can lead to disease and even death. Drug therapy is the most basic and commonly used method for pain relief and management. Interestingly, at present, hundreds of traditional Chinese medicines have been reported to be used for pain relief, most of which are monomer preparations, which have been developed into new painkillers. Corydalis yanhusuo is a representative of one of these medicines and is available for pain relief. AIM OF THE STUDY: This study aims to determine the analgesic effect and the potential targets of the monomers derived from Corydalis yanhusuo, and to explore any possible associated cardiac risk factors. MATERIALS AND METHODS: In this study, four monomers derived from Corydalis yanhusuo (tetrahydropalmatine, corydaline, protopine, dehydrocorydaline) were tested in vivo, using the formalin-induced pain model to determine their analgesic properties. Their potential targets were also determined using whole cell patch clamp recordings and myocardial enzyme assays. RESULTS: The results showed that all monomers showed analgesic activity and inhibited the peak currents, promoted the activation and inactivation phases of Nav1.7, which indicating that Nav1.7 might be involved in the analgesic mechanism of Corydalis yanhusuo. Protopine increased the level of creatine kinase-MB (CK-MB) and inhibited the peak currents, promoted the activation and inactivation phases of Nav1.5, indicating that Nav1.5 might be involved in the cardiac risk associated with protopine treatment. CONCLUSION: These data showed that tetrahydropalmatine produced the best analgesic effect and the lowest cardiac risk. Thus, voltage gated sodium channels (VGSCs) might be the main targets associated with Corydalis yanhusuo. This study, therefore, provides valuable information for future studies and use of traditional Chines medicines for the alleviation of pain.


Assuntos
Analgésicos/farmacologia , Corydalis/química , Medicamentos de Ervas Chinesas/envenenamento , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Analgésicos/química , Analgésicos/isolamento & purificação , Animais , Alcaloides de Berberina/isolamento & purificação , Alcaloides de Berberina/farmacologia , Células CHO , Cricetulus , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Formaldeído , Camundongos , Dor/tratamento farmacológico , Técnicas de Patch-Clamp , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/isolamento & purificação , Canais de Sódio Disparados por Voltagem/efeitos dos fármacos , Canais de Sódio Disparados por Voltagem/metabolismo
17.
Exp Neurol ; 344: 113809, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34256045

RESUMO

Levo-tetrahydropalmatine (l-THP) is mainly derived from the dried tuber of the Papaveraceae plant Corydalis, also called Corydalis B, which is a drug with analgesic, hypnotic, sedative and other effects. Methamphetamine (METH) belongs to the central nervous stimulant and is a highly addictive drug. It is an urgent problem to study the mechanism of methamphetamine neurotoxicity and to search for the therapeutic targets of the METH addiction. This review is aimed to discuss the pharmacological mechanism and the protective effects of l-THP on METH-induced neurotoxicity, and to explore the therapeutic prospects of l-THP for METH addiction to provide an innovative application of l-THP in clinic. It was found that exposure to METH leads to the compulsive drug-seeking and drug-taking behavior, which is ultimately resulted in METH addiction and neurotoxicity. L-THP has the inhibitory effects on the incidence, maintenance and relapse of METH addiction. L-THP can effectively enhance the plasticity of nerve cells and improve the function of nerve cells where brain-derived neurotrophic factor (BDNF) and its pathways play a protective role. Therefore, l-THP has the potential to become an important therapeutic drug for METH addiction and neurotoxicity.


Assuntos
Alcaloides de Berberina/farmacologia , Estimulantes do Sistema Nervoso Central/efeitos adversos , Metanfetamina/efeitos adversos , Síndromes Neurotóxicas/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Animais , Antagonistas de Dopamina/farmacologia , Humanos
18.
Toxicology ; 459: 152853, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34252480

RESUMO

Oxaliplatin (OXA) is a third-generation platinum drug; however, its application is greatly limited due to the severe peripheral neurotoxicity. This study aims to confirm the transport mechanism of OXA and to explore whether L-tetrahydropalmatine (L-THP) would alleviate OXA-induced peripheral neurotoxicity by selectively inhibiting these uptake transporters in vitro and in vivo. Our results revealed that organic cation transporter 2 (OCT2), organic cation/carnitine transporter 1 (OCTN1) and organic cation/carnitine transporter 2 (OCTN2) were involved in the uptake of OXA in dorsal root ganglion (DRG) neurons and mitochondria, respectively. L-THP (1-100 µM) reduced OXA (40 µM) induced cytotoxicity in MDCK-hOCT2 (Madin-Darby canine kidney, MDCK), MDCK-hOCTN1, MDCK-hOCTN2, and rat primary DRG cells, and decreased the accumulation of OXA in above cells and rat DRG mitochondria, but did not affect its efflux from MDCK-hMRP2 cells. Furthermore, Co-administration of L-THP (5-20 mg/kg for mice, 10-40 mg/kg for rats; twice a week, iv or ig) attenuated OXA (8 mg/kg for mice, 4 mg/kg for rats; twice a week, iv) induced peripheral neurotoxicity and reduced the platinum concentration in the DRG. Whereas, L-THP (1-100 µM for cells; 10-20 mg/kg for mice) did not impair the antitumour efficacy of OXA (40 µM for cells; 8 mg/kg for mice) in HT29 tumour-bearing nude mice nor in tumour cells (HT29 and SW620 cells). In conclusion, OCT2, OCTN1 and OCTN2 contribute to OXA uptake in the DRG and mitochondria. L-THP attenuates OXA-induced peripheral neurotoxicity via inhibiting OXA uptake but without impairing the antitumour efficacy of OXA. L-THP is a potential candidate drug to attenuate OXA-induced peripheral neurotoxicity.


Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Alcaloides de Berberina/farmacologia , Proteínas de Transporte/antagonistas & inibidores , Gânglios Espinais/metabolismo , Mitocôndrias/metabolismo , Oxaliplatina/farmacocinética , Oxaliplatina/toxicidade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle , Animais , Comportamento Animal/efeitos dos fármacos , Cães , Gânglios Espinais/efeitos dos fármacos , Células HEK293 , Células HT29 , Humanos , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transportador 2 de Cátion Orgânico/antagonistas & inibidores , Ratos , Membro 5 da Família 22 de Carreadores de Soluto/antagonistas & inibidores , Membro 5 da Família 22 de Carreadores de Soluto/metabolismo , Simportadores/antagonistas & inibidores , Simportadores/metabolismo
19.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071406

RESUMO

Coralyne is a synthetic analog of berberine related to protoberberine-isoquinoline alkaloids. Isoquinoline derivatives and analogs are renowned as potent radiosensitizers with potential medical application. In the present study, we investigated the effect of coralyne on the cell death, cytoskeletal changes and cell cycle progression of irradiated A549 cells. A clonogenic assay revealed that coralyne pretreatment decreased the viability of A549 cells in a time- and dose-dependent manner. Moreover, exposure to coralyne and ionizing radiation (IR) markedly altered the filamentous actin cytoskeletal architecture and integrin-ß binding sites of A549 cells. Treatment with 1-25 µM coralyne in combination with 2 Gy of IR significantly reduced the percentage of cells in G2/M phase compared with 2 Gy IR alone. These results indicate that coralyne is a potent radiosensitizing agent that may find an application in medicine.


Assuntos
Alcaloides de Berberina/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Células A549 , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos da radiação , Humanos , Microscopia Confocal , Radiação Ionizante , Radiossensibilizantes/farmacologia
20.
Phytomedicine ; 90: 153594, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34144869

RESUMO

BACKGROUND: Opioids have been prescribed to reduce suffering from pain and to enhance quality of life. Due to the addictive potential and the lack of other effective alternatives to treat severe acute and chronic pains, opioids remain a serious public health issue. While, opioids directly influence the drug-seeking behavior, tolerance and withdrawal processes, through neuroadaptation, the brain's endogenous opioid system also adapts in the presence of chronic pain and could contribute to the difficulty of treatment. Despite the seemingly obvious interaction between the presence of pain and opioid-abuse, little is known about the underlying mechanisms in the brain. PURPOSE: To review the current understanding of the interaction mechanisms of neurotransmitter circuitries in pain modulation and reward in the brain and the effects of L-tetrahydropalmatine (L-THP) and its metabolites in pain management and opioid use disorder and gain a better insight on the pharmacological profile and in vivo effects of L-THP and its metabolites. METHOD: A detailed literature search on available (preclinical and clinical) studies about the effects of L-THP and its metabolites against drug addiction and chronic pain has been performed. The data was collected using various search engines such as PubMed, ScienceDirect, Google scholar and articles in English up to December 2020 were included in this review. RESULTS: L-THP and its metabolites demonstrated analgesic and anti-addiction effects. Due to their dual pharmacological properties (D1 partial agonist and D2 antagonist) these compounds could be used as molecular tools to provide a better understanding of the interactions between pain and addiction. CONCLUSION: The available data confirms the potential of L-THP and its metabolites to treat both chronic pain and drug addiction. However, further clinical trials are needed to establish safety and efficacy.


Assuntos
Alcaloides de Berberina , Dor Crônica , Transtornos Relacionados ao Uso de Opioides , Analgésicos Opioides/efeitos adversos , Alcaloides de Berberina/farmacologia , Dor Crônica/tratamento farmacológico , Humanos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Qualidade de Vida
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