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1.
Oxid Med Cell Longev ; 2021: 6647107, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33953834

RESUMO

Acetylshikonin, a naphthoquinone, is a pigment compound derived from Arnebia sp., which is known for its anti-inflammatory potential. However, its anticarcinogenic effect has not been well investigated. Thus, in this study, we focused on investigating its apoptotic effects against HCT-15 and LoVo cells, which are human colorectal cancer cells. MTT assay, cell counting assay, and colony formation assay have shown acetylshikonin treatment induced cytotoxic and antiproliferative effects against colorectal cancer cells in a dose- and time-dependent manner. DNA fragmentation was observed via terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Also, the increase of subG1 phase in cell cycle arrest assay and early/late apoptotic rates in annexin V/propidium iodide (PI) double staining assay was observed, which indicates an apoptotic potential of acetylshikonin against colorectal cancer cells. 2',7'-Dichlorofluorescin diacetate (DCF-DA) staining was used to evaluate reactive oxygen species (ROS) generation in acetylshikonin-treated colorectal cancer cells. Fluorescence-activated cell sorting (FACS) analysis showed that acetylshikonin induced an increase in reactive oxygen species (ROS) levels and apoptotic rate in a dose- and time-dependent manner in HCT-15 and LoVo cells. In contrast, cotreatment with N-acetyl cysteine (NAC) has reduced ROS generation and antiproliferative effects in colorectal cancer cells. Western blotting analysis showed that acetylshikonin treatment induced increase of cleaved PARP, γH2AX, FOXO3, Bax, Bim, Bad, p21, p27, and active forms of caspase-3, caspase-7, caspase-9, caspase-6, and caspase-8 protein levels, while those of inactive forms were decreased. Also, the expressions of pAkt, Bcl-2, Bcl-xL, peroxiredoxin, and thioredoxin 1 were decreased. Furthermore, western blotting analysis of cytoplasmic and nuclear fractionated proteins showed that acetylshikonin treatment induced the nuclear translocation of FOXO3, which might result from DNA damage by the increased intracellular ROS level. This study represents apoptotic potential of acetylshikonin against colorectal cancer cells via translocation of FOXO3 to the nucleus and upregulation of ROS generation.


Assuntos
Antraquinonas/uso terapêutico , Pontos de Checagem do Ciclo Celular/genética , Neoplasias Colorretais/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Proteína Forkhead Box O3/metabolismo , Antraquinonas/farmacologia , Apoptose , Proliferação de Células , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Espécies Reativas de Oxigênio
2.
Molecules ; 26(6)2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33808969

RESUMO

BACKGROUND: This study reports on the cytotoxic properties of nordamnacanthal and damnacanthal, isolated from roots of Morinda elliptica on T-lymphoblastic leukaemia (CEM-SS) cell lines. METHODS: MTT assay, DNA fragmentation, ELISA and cell cycle analysis were carried out. RESULTS: Nordamnacanthal and damnacanthal at IC50 values of 1.7 µg/mL and10 µg/mL, respectively. At the molecular level, these compounds caused internucleosomal DNA cleavage producing multiple 180-200 bp fragments that are visible as a "ladder" on the agarose gel. This was due to the activation of the Mg2+/Ca2+-dependent endonuclease. The induction of apoptosis by nordamnacanthal was different from the one induced by damnacanthal, in a way that it occurs independently of ongoing transcription process. Nevertheless, in both cases, the process of dephosphorylation of protein phosphates 1 and 2A, the ongoing protein synthesis and the elevations of the cytosolic Ca2+ concentration were not needed for apoptosis to take place. Nordamnacanthal was found to have a cytotoxic effect by inducing apoptosis, while damnacanthal caused arrest at the G0/G1 phase of the cell cycle. CONCLUSION: Damnacanthal and nordamnacanthal have anticancer properties, and could act as potential treatment for T-lymphoblastic leukemia.


Assuntos
Aldeídos/farmacologia , Antraquinonas/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Morinda/química , Plantas Medicinais/química , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Aldeídos/isolamento & purificação , Antraquinonas/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Fragmentação do DNA , Endodesoxirribonucleases/metabolismo , Humanos , Raízes de Plantas/química , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo
3.
Molecules ; 26(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802855

RESUMO

Inflammatory bowel disease (IBD) is an immune disorder that develops due to chronic inflammation in several cells. It is known that colorectal and T cells are mainly involved in the pathogenesis of IBD. Chrysophanol is an anthraquinone family member that possesses several bioactivities, including anti-diabetic, anti-tumor, and inhibitory effects on T cell activation. However, it is unknown whether chrysophanol suppresses the activity of colorectal cells. In this study, we found that chrysophanol did not induce cytotoxicity in HT-29 colorectal cells. Pre-treatment with chrysophanol inhibited the mRNA levels of pro-inflammatory cytokines in tumor necrosis factor-α (TNF-α)-stimulated HT-29 cells. Western blot analysis revealed that pre-treatment with chrysophanol mitigates p65 translocation and the mitogen-activated protein kinase (MAPK) pathway in activated HT-29 cells. Results from the in vivo experiment confirmed that oral administration of chrysophanol protects mice from dextran sulfate sodium (DSS)-induced IBD. Chrysophanol administration attenuates the expression of pro-inflammatory cytokines in colon tissues of the DSS-induced IBD model. In addition, we found that oral administration of chrysophanol systemically decreased the expression of effector cytokines from mesenteric lymph nodes. Therefore, these data suggest that chrysophanol has a potent modulatory effect on colorectal cells as well as exhibiting a beneficial potential for curing IBD in vivo.


Assuntos
Antraquinonas/administração & dosagem , Antraquinonas/farmacologia , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Administração Oral , Animais , Antraquinonas/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Colo/citologia , Colo/efeitos dos fármacos , Colo/metabolismo , Neoplasias Colorretais/patologia , Citocinas/genética , Citocinas/metabolismo , Sulfato de Dextrana/toxicidade , Feminino , Células HT29 , Humanos , Doenças Inflamatórias Intestinais/induzido quimicamente , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
4.
Chem Biol Interact ; 341: 109449, 2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-33798507

RESUMO

BACKGROUND: COVID-19, a severe global pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged as one of the most threatening transmissible disease. As a great threat to global public health, the development of treatment options has become vital, and a rush to find a cure has mobilized researchers globally from all areas. SCOPE AND APPROACH: This review focuses on deciphering the potential of different secondary metabolites from medicinal plants as therapeutic options either as inhibitors of therapeutic targets of SARS-CoV-2 or as blockers of viral particles entry through host cell receptors. The use of medicinal plants containing specific phytomoieties could be seen in providing a safer and long-term solution for the population with lesser side effects. Key Findings and Conclusions: Considering the high cost and time-consuming drug discovery process, therapeutic repositioning of existing drugs was explored as treatment option in COVID-19, however several molecules have been retracted as therapeutics either due to no positive outcomes or the severe side effects. These effects call for exploring the alternate treatment options which are therapeutically effective as well as safe. Keeping this in mind, phytopharmaceuticals derived from medicinal plants could be explored as important resources in the development of COVID-19 treatment, as their role in the past for treatment of viral diseases like HIV, MERS-CoV, and influenza has been well reported. Considering this fact, different phytoconstituents such as flavonoids, alkaloids, tannins and glycosides etc. Possessing antiviral properties against coronaviruses and possessing potential against SARS-CoV-2 have been reviewed in the present work.


Assuntos
Antivirais/farmacologia , Compostos Fitoquímicos/farmacologia , Alcaloides/química , Alcaloides/farmacologia , Antraquinonas/química , Antraquinonas/farmacologia , Antivirais/química , Flavonoides/química , Flavonoides/farmacologia , Humanos , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Compostos Fitoquímicos/química , Plantas Medicinais/química , Plantas Medicinais/metabolismo , Saponinas/química , Saponinas/farmacologia , Metabolismo Secundário
5.
Eur J Pharmacol ; 900: 174020, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33741381

RESUMO

Gastric cancer is one of the most common and deadly cancers among men and women and is the third leading cause of cancer mortality worldwide. Thus, discovering and developing novel therapeutics for gastric cancer has become a global priority. In this study, we synthesized two novel anthraquinone-based aspirin derivatives, Asp-X3 and Asp-X3-CH3, with therapeutic potential for gastric cancer. The structures of the two compounds were determined by 1D, 2D-NMR, and High-Resolution Mass (HRSM). Asp-X3 and Asp-X3-CH3 could inhibit the growth of gastric cancer cells (SGC7901), yielding IC50 values 10-fold lower than that of Aspirin. Asp-X3 and Asp-X3-CH3 were less toxic to gastric mucosal cells, yielding IC50 values that were about 2-fold higher than the corresponding IC50 values determined with SGC7901 cells. Asp-X3-CH3 and Asp-X3 also induced SGC7901 cells to undergo apoptosis, yielding apoptotic rates that were about twice the rate induced by Aspirin. Asp-X3-CH3 did not cause significant loss of COX-1 expression in gastric mucosal cells, whereas Asp-X3 and Aspirin both caused significant loss of COX-1 expression as demonstrated by Western blot, consistent with their effects on the content of PGE2 in these cells as determined by ELISA assay. However, both Asp-X3-CH3 and Asp-X3 exerted a similar effect on the level of COX-2 in gastric cancer cells, causing as much as 90% and 95% reduction in COX-2 expression, respectively. Taken together, the results suggested that Asp-X3-CH3 and Asp-X3 were potentially better agents than Aspirin for the inhibition of gastric cancer cell growth, but Asp-X3-CH3 was more effective.


Assuntos
Antraquinonas/síntese química , Antraquinonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Aspirina/análogos & derivados , Aspirina/farmacologia , Neoplasias Gástricas/prevenção & controle , Apoptose/efeitos dos fármacos , Aspirina/síntese química , Linhagem Celular Tumoral , Ciclo-Oxigenase 1/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/metabolismo , Mucosa Gástrica/citologia , Mucosa Gástrica/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Neoplasias Gástricas/induzido quimicamente , Relação Estrutura-Atividade
6.
Mar Drugs ; 19(2)2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33673168

RESUMO

Coculture is a productive technique to trigger microbes' biosynthetic capacity by mimicking the natural habitats' features principally by competition for food and space and interspecies cross-talks. Mixed cultivation of two Red Sea-derived actinobacteria, Actinokineospora spheciospongiae strain EG49 and Rhodococcus sp. UR59, resulted in the induction of several non-traced metabolites in their axenic cultures, which were detected using LC-HRMS metabolomics analysis. Antimalarial guided isolation of the cocultured fermentation led to the isolation of the angucyclines actinosporins E (1), H (2), G (3), tetragulol (5) and the anthraquinone capillasterquinone B (6), which were not reported under axenic conditions. Interestingly, actinosporins were previously induced when the axenic culture of the Actinokineospora spheciospongiae strain EG49 was treated with signalling molecule N-acetyl-d-glucosamine (GluNAc); this finding confirmed the effectiveness of coculture in the discovery of microbial metabolites yet to be discovered in the axenic fermentation with the potential that could be comparable to adding chemical signalling molecules in the fermentation flask. The isolated angucycline and anthraquinone compounds exhibited in vitro antimalarial activity and good biding affinity against lysyl-tRNA synthetase (PfKRS1), highlighting their potential developability as new antimalarial structural motif.


Assuntos
Actinobacteria/metabolismo , Antimaláricos/isolamento & purificação , Metabolômica , Rhodococcus/metabolismo , Antraquinonas/isolamento & purificação , Antraquinonas/farmacologia , Antimaláricos/farmacologia , Cromatografia Líquida , Técnicas de Cocultura , Fermentação , Oceano Índico , Espectrometria de Massas
7.
Toxicol Appl Pharmacol ; 418: 115481, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33722666

RESUMO

Since its discovery, anthraquinone has become very valuable as a lead compound in the development of anti-cancer drugs. Previously, we designed and synthesized a new type of amide anthraquinone derivative (1-nitro-2-acylanthraquinone glycine, C10) with good activity against colon cancer. However, its effect and the underlying mechanism are unclear. In this study, C10 significantly inhibited the proliferation of HCT116 and HT29 colon cancer cells by blocking the cell cycle at the G2/M phase. C10 also plays a role in cell cycle arrest by reducing the protein and gene expression levels of cyclin B1 and its downstream signaling molecule cyclin-dependent kinase (CDK1). In addition, molecular docking studies showed that C10 has high affinity for Jak2, the first target in the cell cycle-related Jak2/Stat3 signaling pathway. Furthermore, C10 downregulated the expression of Jak2/Stat3 signaling pathway-related signaling molecules proteins and genes, and up-regulated the expression of PIAS-3, the upstream signaling molecule of Stat3, thereby down-regulating Stat3 phosphorylation. C10 reversed the expression of Jak2/Stat3 signaling pathway-related molecules activated by IL-6. Overall, our results indicate for the first time that C10 induces cell cycle arrest and inhibits cell proliferation by inhibiting the Jak2/Stat3 signaling pathway. This study provides new insights into the potential role of Jak2/Stat3 in the regulating cell cycle-related signaling pathways that mediate the inhibitory effects of C10 on colon cancer cell proliferation.


Assuntos
Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Janus Quinase 2/metabolismo , Fator de Transcrição STAT3/metabolismo , Neoplasias do Colo/enzimologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HT29 , Humanos , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Fosforilação , Proteínas Inibidoras de STAT Ativados/genética , Proteínas Inibidoras de STAT Ativados/metabolismo , Transdução de Sinais , Regulação para Cima
8.
J Nat Med ; 75(3): 520-531, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33620670

RESUMO

Senna siamea has been used as an antidiabetic drug since antiquity. With regard to traditional Thai medicine, the use of S. siamea was described for diabetes therapy. To understand the molecular mechanism regarding insulin resistance. Pure compounds were isolated from wood extract. We studied their biological activities on insulin-resistance using an in vivo zebrafish model. We also performed an in silico study; molecular docking, and in vitro study by taking advantage of the enzyme inhibitory activities of α-glucosidase, PTP1B, and DPP-IV. Based on the preliminary investigation that ethyl acetate and ethanol extracts have potent effects against insulin resistance on zebrafish larvae, five compounds were isolated from two fractions following: resveratrol, piceatannol, dihydropiceatannol, chrysophanol, and emodin. All of the isolated compounds had anti-insulin resistance effects on zebrafish larvae. Resveratrol, piceatannol, and dihydropiceatannol also demonstrated inhibitory effects against α-glucosidase. Chrysophanol and emodin inhibited PTP1B activity, while resveratrol showed a DPP-IV inhibition effect via the molecular docking. The results of enzyme assay were similar. In conclusions, S. siamea components demonstrated effects against insulin resistance. The chemical structure displayed identical biological activity to that of the compounds. Therefore, S. siamea wood extract and their components are potential therapeutic options in the treatment of diabetes.


Assuntos
Hipoglicemiantes/farmacologia , Resistência à Insulina , Extratos Vegetais/farmacologia , Senna (Planta)/química , Animais , Antraquinonas/farmacologia , Diabetes Mellitus , Dipeptidil Peptidase 4/metabolismo , Emodina/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Resveratrol/farmacologia , Estilbenos/farmacologia , Relação Estrutura-Atividade , Tailândia , Madeira/química , Peixe-Zebra/metabolismo , alfa-Glucosidases/metabolismo
9.
Molecules ; 26(3)2021 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-33572569

RESUMO

The anticancer activities of Rubia cordifolia and its constituents have been reported earlier, but their influence on the crosstalk of complex cancer-related signaling metabolic pathways (i.e., transcription factors; TF) has not yet been fully investigated. In this study, R. cordifolia root extract was subjected to the cancer signaling assay based bioactivity-guided fractionation, which yielded the following compounds viz., three anthraquinones, namely alizarin (1), purpurin (2), and emodin (3); two lignans, namely eudesmin (4) and compound 5; and two cyclic hexapeptides, namely deoxybouvardin RA-V (6), and a mixture of 6+9 (RA-XXI). The structures of the isolated compounds were determined by NMR spectroscopy and HRESIMS. The isolated compounds 1, 2, 3, 6, and a mixture of 6+9 were tested against a panel of luciferase reporter genes that assesses the activity of a wide-range of cancer-related signaling pathways. In addition, reference anthraquinones viz., chrysophanol (11), danthron (12), quinizarin (13), aloe-emodin (14), and α-lapachone (15) were also tested. Among the tested compounds, the cyclic hexapeptide 6 was found to be very active against several signaling pathways, notably Wnt, Myc, and Notch with IC50 values of 50, 75, and 93 ng/mL, respectively. Whereas, the anthraquinones exhibited very mild or no inhibition against these signaling pathways. Compound 6 being the most active, we tested it for stability in simulated intestinal (SIF) and gastric fluids (SGF), since the stability in biological fluid is a key short-coming of cyclic hexapeptides. The anticancer activity of 6 was found to remain unchanged before and after the treatment of simulated gastric/intestinal fluids, indicating that RA-V was stable. As a result, it could be bioavailable when orally used in therapeutics and possibly a drug candidate for cancer treatment. The mechanism for the preferential inhibition of these pathways and the possible crosstalk effect with other previously reported signaling pathways has been discussed.


Assuntos
Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Peptídeos Cíclicos/farmacologia , Rubia/química , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos
10.
Food Chem ; 342: 128378, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33508903

RESUMO

Rheum ribes L. (Rhubarb) is one of the most important edible medicinal plants in the Eastern Anatolia region and is called "Iskin" by local people. Resveratrol and 6-O-methylalaternin were isolated from the Rhubarb for the first time in addition to well-known secondary metabolites including emodin, aloe-emodin, ß-sitosterol and rutin. The new semi-synthetic anthraquinone derivatives with the NαFmoc-l-Lys and ethynyl group were synthesized from the isolated anthraquinones emodin and aloe-emodin of Rhubarb to increase the bioactivities. Aloe-emodin derivative with NαFmoc-l-Lys shows the highest inhibition values by 94.11 ± 0.12 and 82.38 ± 0.00% against HT-29 and HeLa cell lines, respectively, at 25 µg/mL. Further, modification of the aloe-emodin with both the ethynyl and the NαFmoc-l-Lys groups showed an antioxidant activity-enhancing effect. From molecular docking studies, the relative binding energies of the emodin and aloe-emodin derivatives to human serum albumin ranged from -7.30 and -10.62 kcal/mol.


Assuntos
Antraquinonas/química , Antineoplásicos/síntese química , Resveratrol/química , Rheum/química , Antraquinonas/síntese química , Antraquinonas/isolamento & purificação , Antraquinonas/metabolismo , Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Emodina/química , Emodina/isolamento & purificação , Emodina/metabolismo , Emodina/farmacologia , Humanos , Simulação de Acoplamento Molecular , Componentes Aéreos da Planta/química , Componentes Aéreos da Planta/metabolismo , Resveratrol/isolamento & purificação , Resveratrol/farmacologia , Rheum/metabolismo , Albumina Sérica/química , Albumina Sérica/metabolismo
11.
Ecotoxicol Environ Saf ; 205: 111328, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32950805

RESUMO

Understanding the degradation of pentachlorophenol (PCP) by indigenous microorganisms stimulated by an electron donor and shuttle in paddy soil, and the influences of PCP/electron donor/shuttle on the native microbial community are important for biodegradation and ecological and environmental safety. Previous studies focused on the kinetics and the microbial actions of PCP degradation, however, the effects of toxic and antimicrobial PCP and electron donor/shuttle on the microbial community diversity and composition in paddy soil are poorly understood. In this study, the effects of PCP, an electron donor (lactate), and the electron shuttle (anthraquinone-2, 6-disulfonate, AQDS) on the microbial community in paddy soil were investigated. The results showed that the presence of PCP reduced the microbial diversity compared to the control during PCP degradation, while increased the microbial diversity was observed in response to lactate and AQDS. The addition of PCP stimulated the microorganisms involved in PCP dechlorination, including Clostridium, Desulfitobacterium, Pandoraea, and unclassified Veillonellaceae, which were dormant in raw soil without PCP stress. In all of the treatments with PCP, the addition of lactate or AQDS enhanced PCP dechlorination by stimulating the growth of functional groups involved in PCP dechlorination and by changing the microbial community during dechlorination process. The microbial community tended to be uniform after complete PCP degradation (28 days). However, when lactate and AQDS were present simultaneously in PCP-contaminated soil, lactate acted as a carbon source or electron donor to promote the activities of microbial community, and AQDS changed the redox potential because of the production of reduced AQDS. These findings enhance our understanding of the effect of PCP and a biostimulation method for PCP biodegradation in soil ecosystems at the microbial community level, and suggest the appropriate selection of an electron donor/shuttle for accelerating the bioremediation of PCP-contaminated soils.


Assuntos
Microbiota/efeitos dos fármacos , Pentaclorofenol/toxicidade , Microbiologia do Solo , Poluentes do Solo/toxicidade , Solo/química , Antraquinonas/farmacologia , Biodegradação Ambiental , Transporte de Elétrons , Ácido Láctico/farmacologia
12.
J Pharmacol Sci ; 144(3): 172-182, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32811746

RESUMO

Hepatitis B virus X protein (HBx) and hepatic stellate cells (HSCs) are critical for liver fibrosis development. Anti-fibrosis occurs via reversion to quiescent-type HSCs or clearance of HSCs via apoptosis or ferroptosis. We aimed to elucidate the role of chrysophanol in rat HSC-T6 cells expressing HBx and investigate whether chrysophanol (isolated from Rheum palmatum rhizomes) influences cell death via ferroptosis in vitro. Analysis of lipid reactive oxygen species (ROS), Bip, CHOP, p-IRE1α, GPX4, SLC7A11, α-SMA, and CTGF showed that chrysophanol attenuated HBx-repressed cell death. Chrysophanol can impair HBx-induced activation of HSCs via endoplasmic reticulum stress (ER stress) and ferroptosis-dependent and GPX4-independent pathways.


Assuntos
Antraquinonas/farmacologia , Antraquinonas/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Células Estreladas do Fígado/patologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/etiologia , Fitoterapia , Transativadores/efeitos adversos , Proteínas Virais Reguladoras e Acessórias/efeitos adversos , Animais , Antraquinonas/isolamento & purificação , Linhagem Celular , Fibrose , Células Estreladas do Fígado/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo
13.
Cell Prolif ; 53(8): e12871, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32597546

RESUMO

OBJECTIVES: Osteonecrosis of the femoral head (ONFH), largely caused by alcohol abuse, is a refractory bone disease characterized by the impaired capacity of osteogenic differentiation of bone mesenchymal stem cells (BMSCs), as well as the disordered adipocyte accumulation. Chrysophanic acid (CPA) is a natural anthraquinone which has lipid regulation and bone protection capacity. The aim of this study was to reveal the potential function of CPA and the underlying mechanisms for the alcohol-induced ONFH. MATERIALS AND METHODS: The effects of alcohol and CPA on BMSCs were investigated by cell proliferation, induced differentiation assays and immunofluorescent staining. Meanwhile, the function of PI3K/AKT and AMPK pathway was investigated in the process of osteogenic and adipogenic differentiation, respectively. Furthermore, we established the rat model of alcohol-induced ONFH to reveal the pharmacotherapeutic effect of CPA in vivo using radiographical and histopathological methods. RESULTS: In vitro, alcohol significantly inhibited the proliferation and osteogenic differentiation of BMSCs but stimulated the adipogenic differentiation. However, CPA could counteract the anti-osteogenesis of alcohol partly via PI3K/AKT pathway and retard the promotion of alcohol-induced adipogenesis via AMPK pathway. In vivo, radiographical and histopathological findings showed that CPA could alleviate alcohol-induced ONFH and substantially restore the bone volume. CONCLUSIONS: We demonstrated that CPA ameliorated alcohol-induced ONFH possibly via regulating the differentiation tendency of BMSCs. Hence, CPA may become a beneficial herb extract to alleviate alcohol-induced ONFH.


Assuntos
Antraquinonas/farmacologia , Proliferação de Células/efeitos dos fármacos , Cabeça do Fêmur/patologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteonecrose/patologia , Adipogenia/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Cabeça do Fêmur/efeitos dos fármacos , Células-Tronco Mesenquimais/citologia , Ratos Sprague-Dawley
14.
Chin J Nat Med ; 18(6): 425-435, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32503734

RESUMO

Emodin (1, 3, 8-trihydroxy-6-methylanthraquinone) is a derived anthraquinone compound extracted from roots and barks of pharmaceutical plants, including Rheum palmatum, Aloe vera, Giant knotweed, Polygonum multiflorum and Polygonum cuspidatum. The review aims to provide a scientific summary of emodin in pharmacological activities and toxicity in order to identify the therapeutic potential for its use in human specific organs as a new medicine. Based on the fundamental properties, such as anticancer, anti-inflammatory, antioxidant, antibacterial, antivirs, anti-diabetes, immunosuppressive and osteogenesis promotion, emodin is expected to become an effective preventive and therapeutic drug of cancer, myocardial infarction, atherosclerosis, diabetes, acute pancreatitis, asthma, periodontitis, fatty livers and neurodegenerative diseases. This article intends to provide a novel insight for further development of emodin, hoping to reveal the potential of emodin and necessity of further studies in this field.


Assuntos
Antraquinonas/farmacologia , Antraquinonas/toxicidade , Emodina/farmacologia , Emodina/toxicidade , Extratos Vegetais/farmacologia , Extratos Vegetais/toxicidade , Humanos , Estrutura Molecular , Casca de Planta , Raízes de Plantas
15.
J Med Microbiol ; 69(5): 689-696, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32375980

RESUMO

Introduction. Rhein (4, 5-dihydroxyanthraquinone-2-carboxylic acid) has various properties, including anti-inflammatory, antioxidant and anticancer activities. However, the mechanism underlying the role of rhein in antimicrobial activity remains largely unknown.Aim. This study aims to identify potential natural compounds of rhein that are capable of inhibiting Cutibacterium acnes and elucidate the effects of rhein on NADH dehydrogenase-2 activity in C. acnes.Methodology. The anti-C. acnes activity of compounds was analysed using minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), the paper disc diffusion test and the checkerboard dilution test. To check whether rhein was inhibitory, putative type II NADH dehydrogenase (NDH-2) of C. acnes was analysed, cloned and expressed in Escherichia coli, and then NDH-2 purification was assessed with Ni-NTA before rhein inhibition of NADH dehydrogenase-2 activity was checked with ferricyanide [K3Fe(CN)6] as a substrate.Results. The results showed that the MIC of rhein against C. acnes was 6.25 µg ml-1, while the MBC was 12.5 µg ml-1, and there was a 38 mm inhibition zone in the paper disc diffusion test. Rhein showed an additive two- to fourfold reduction of the MIC value with four antibiotics on the checkerboard dilution test. The purified NADH dehydrogenase gene product showed a size of approximately 51 kDa and had a V max of 23 µmol and a K m of 280 µm. The inhibitory effect of rhein against NADH dehydrogenase-2 activity was non-competitive with ferricyanide [K3Fe(CN)6] with a K i value of 3.5-4.5 µm.Conclusion. This study provided evidence of the inhibitory effects of rhein on the growth of C. acnes by blocking of NADH dehydrogenase-2 activity. This mechanism of inhibitory activity in the reduction of ROS formation and ATP productivity should be further tested in C. acnes and the question of whether rhein inhibits the natural growth of C. acnes should be investigated.


Assuntos
Antraquinonas/farmacologia , Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Infecções por Bactérias Gram-Positivas/microbiologia , NADH Desidrogenase/antagonistas & inibidores , Propionibacterium acnes/efeitos dos fármacos , Propionibacterium acnes/enzimologia , Antraquinonas/uso terapêutico , Antibacterianos/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Humanos , Cinética , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Propionibacterium acnes/crescimento & desenvolvimento , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes
16.
Sci Rep ; 10(1): 4888, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32184434

RESUMO

Although fibrosis depicts a reparative mechanism, maladaptation of the heart due to excessive production of extracellular matrix accelerates cardiac dysfunction. The anthraquinone Rhein was examined for its anti-fibrotic potency to mitigate cardiac fibroblast-to-myofibroblast transition (FMT). Primary human ventricular cardiac fibroblasts were subjected to hypoxia and characterized with proteomics, transcriptomics and cell functional techniques. Knowledge based analyses of the omics data revealed a modulation of fibrosis-associated pathways and cell cycle due to Rhein administration during hypoxia, whereas p53 and p21 were identified as upstream regulators involved in the manifestation of cardiac fibroblast phenotypes. Mechanistically, Rhein acts inhibitory on HDAC classes I/II as enzymatic inhibitor. Rhein-mediated cellular effects were linked to the histone deacetylase (HDAC)-dependent protein stabilization of p53 under normoxic but not hypoxic conditions. Functionally, Rhein inhibited collagen contraction, indicating anti-fibrotic property in cardiac remodeling. This was accompanied by increased abundance of SMAD7, but not SMAD2/3, and consistently SMAD-specific E3 ubiquitin ligase SMURF2. In conclusion, this study identifies Rhein as a novel potent direct HDAC inhibitor that may contribute to the treatment of cardiac fibrosis as anti-fibrotic agent. As readily available drug with approved safety, Rhein constitutes a promising potential therapeutic approach in the supplemental and protective intervention of cardiac fibrosis.


Assuntos
Antraquinonas/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 2/antagonistas & inibidores , Adulto , Western Blotting , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Proteína Smad7/genética , Proteína Smad7/metabolismo , Transcriptoma/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
17.
Carbohydr Res ; 490: 107958, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32120022

RESUMO

Rhein is a potential antitumor agent, but the poor water-solubility restricts its clinical applicability. ß-cyclodextrin-drug conjugates provide a possibility to improve the water-solubility of rhein and thereby enhance its bioavailability. A novel ß-cyclodextrin-rhein conjugate (ß-CD-RH) was synthesized by covalently link ß-cyclodextrin with rhein through a 1,8-diamino-3,6-dioxaoctane linker. The structure of ß-CD-RH was characterized by 1H NMR, FT-IR, Maldi-tof MS etc. The inclusion style of ß-CD-RH in water was detected by 2D NMR. The 2D ROESY spectrum provided details of the rhein moiety encapsulated in the ß-CD cavity. The water-solubility of ß-CD-RH is up to 3.24 µmol/mL ß-CD-RH exhibited higher cytotoxicity than rhein and rhein/ß-CD mixture against Hela cells. Our work provides a new way for the preparation of novel ß-CD-drug conjugate.


Assuntos
Antraquinonas/farmacologia , Antineoplásicos/farmacologia , beta-Ciclodextrinas/química , Antraquinonas/química , Antineoplásicos/química , Disponibilidade Biológica , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células HeLa , Humanos , Estrutura Molecular , Espectroscopia de Prótons por Ressonância Magnética , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Água/química
18.
Fish Shellfish Immunol ; 99: 331-341, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32084536

RESUMO

The present study was investigated the dietary administration of cassic acid (CA) on growth, innate immunity, transcription profiles of estrogen and follicle-stimulating hormones as well as lysozyme enzyme determined in Clarias gariepinus against Edwardsiella tarda. The weight gain (WG), protein efficacy ratio (PER), and feed conversion ratio (FCR) were significantly improved in infected fish fed dietary administration with CA at 5 and 10 mg kg-1 diets. The survival is higher (96.7% and 98.3%) in the infected groups fed at 5 and 10 mg kg-1 CA diets. The red (RBC) and white (WBC) blood cells, hemoglobin (Hb), and packed cell volume (PCV) was found significantly high in the infected fish feeding at 5 and 10 mg kg-1 CA diets. Total protein and albumin were significantly increased with 5 and 10 mg kg-1 CA diets among weeks 1-4 while the globulin and albumin: globulin ratio increased of these diet only after week 2. The phagocytic and respiratory burst activities were enhanced statistically the infected fish fed at 10 mg kg-1 CA diet group whereas the production of superoxide anion (SOA) and nitric oxide (NO) were significantly increased at 5 and 10 mg kg-1 CA diets. The lymphocyte proliferation and myeloperoxidase (MPO) activity were significantly high the infected fish when fed at 5 and 10 mg kg-1 CA diets after 2nd week whereas the alternate complement activity (ACP), generation of reactive oxygen species (ROS), and lysozyme activity (Lyz) were observed at 5 and 10 mg kg-1 CA diets among weeks 1-4. The accumulative mortality was 10% in infected fish fed at 1 and 5 mg kg-1 CA diets whereas 15% mortality found with 10 mg kg-1 CA diet. The highest levels of estrogen receptor alpha (ERα) mRNA expression found in gonad while the highest levels of follicle stimulating hormone-beta subunit (FSH-ß) mRNA expression found in testis of the infected fish given at 5 and 10 mg kg-1 CA diets. The up-regulation of chick-type lysozyme (c-Lyz) mRNA was observed at 5 and 10 mg kg-1 CA diets after 2nd week while goose-type lysozyme (g-Lyz) mRNA was up-regulation amongst weeks 1-4 of these diets. The present study suggested that E. tarda challenged fish after feeding with 5 and 10 mg kg-1 CA diets did not affect growth and hemato-biochemical parameter, but it enhanced nonspecific immune system and improving ERα, FSH-ß, c-Lyz, and g-Lyz mRNA expression in C. gariepinus against E. tarda.


Assuntos
Antraquinonas/farmacologia , Peixes-Gato , Edwardsiella tarda , Infecções por Enterobacteriaceae/veterinária , Doenças dos Peixes/prevenção & controle , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Antraquinonas/química , Clonagem Molecular , Dieta/veterinária , Suplementos Nutricionais , Infecções por Enterobacteriaceae/microbiologia , Inibidores Enzimáticos , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Regulação da Expressão Gênica/efeitos dos fármacos
19.
Dalton Trans ; 49(5): 1613-1619, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31942585

RESUMO

We herein designed two new PtIV prodrugs of oxoplatin (cis,cis,cis-[PtCl2(NH3)2(OH)2]), [PtIVCl2(NH3)2(O2C-FA)2] (Pt-2) and [PtIVCl2(NH3)2(O2C-RH)2] (Pt-3), by conjugating with ferulic acid (FA-COOH) and rhein (RH-COOH) which have well-known biological activities. Three other Pt(iv) complexes of [PtIVCl2(NH3)2(O2C-BA)2] (Pt-1), [PtIVCl2(NH3)2(O2C-CA)2] (Pt-4) and [PtIVCl2(NH3)2(O2C-TCA)2] (Pt-5) (where BA-COOH = benzoic acid, CA-COOH = crotonic acid and TCA-COOH = trans-cinnamic acid) were also prepared for the comparative study. Like most PtIV prodrug complexes, the cytotoxicity of Pt-3 containing the biologically active rhein (RH-COOH) ligand against lung carcinoma (A549 and A549/DDP) cells was higher than those of Pt-1, Pt-2, Pt-4, cisplatin and Pt-5. Moreover, the cytotoxicity of Pt-3 in HL-7702 normal cells was lower than those of PtIV derivatives bearing BA-COOH, FA-COOH, TCA-COOH and CA-COOH ligands. The highly efficacious Pt-2 and Pt-3 were found to accumulate strongly in the A549/DDP cells, with the prodrug Pt-3 showing highest levels of penetration into the mitochondria. The prodrug Pt-3 effectively entered the A549/DDP cells and caused mitochondrial damage, significantly greater than Pt-2. In addition, the prodrug Pt-3 exhibited higher antitumor efficacy (inhibition rates (IR) = 67.45%) than Pt-2 (28.12%) and cisplatin (33.05%) in the A549/DDP xenograft mouse model. Thus, the prodrug Pt-3 containing the rhein (RH-COOH) ligand is a promising candidate drug targeting the mitochondria.


Assuntos
Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Cisplatino/análogos & derivados , Ácidos Cumáricos/farmacologia , Compostos Organoplatínicos/farmacologia , Pró-Fármacos/farmacologia , Células A549 , Animais , Antraquinonas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Cisplatino/farmacologia , Ácidos Cumáricos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade
20.
Biomed Pharmacother ; 123: 109779, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31918211

RESUMO

Staphylococcus xylosus (S. xylosus) is one of the emerging pathogens causing bovine mastitis with high rate of isolation in most of the reported clinical and field cases. To verify the role of glutamine synthetase (GS) in the pathogenesis of S. xylosus, we evaluated the virulence level of the wild-type strain and its glnA mutant strain in biofilm assays in vitro and murine infection model in vivo. From the results, it was observed that the glnA mutant strain was attenuated and could reduce tissue damage. 1-Hydroxyanthraquinone (1-HAQ) is a kind of anthraquinones, it exhibited a significant inhibitory effect on the growth of S. xylosus and biofilm formation in vitro and provided anti-inflammatory effects in vivo. In addition, the rate at which it inhibits the biofilm, inflammatory factors, and CFU of wild-type strains were significantly higher than that of the mutant strains, indicating that 1-hAQ might have pharmacological effects against S. xylosus through the regulation of GS protein. The effect of 1-hAQ on GS was further confirmed by the down-regulation of glnA expression, reduced GS activity, Gln content and the results of molecular docking. Taken together, these findings suggest that 1-hAQ facilitated a significant attenuation of S. xylosus pathogenicity by regulating the GS protein: a vital virulence factor. Therefore, it can be inferred that 1-hAQ may serve as a potential source of organic compound for the development of novel alternative drugs in mitigating the menace of bovine mastitis.


Assuntos
Antraquinonas/farmacologia , Antibacterianos/farmacologia , Glutamato-Amônia Ligase/metabolismo , Staphylococcus/enzimologia , Staphylococcus/patogenicidade , Fatores de Virulência/metabolismo , Animais , Antraquinonas/química , Antraquinonas/uso terapêutico , Antibacterianos/uso terapêutico , Biofilmes/efeitos dos fármacos , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Feminino , Mastite/tratamento farmacológico , Mastite/microbiologia , Mastite/patologia , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Staphylococcus/efeitos dos fármacos , Staphylococcus/crescimento & desenvolvimento
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