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1.
Molecules ; 26(19)2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34641608

RESUMO

The effect of spontaneous fermentation by lactic acid bacteria on the extraction yield of bioactive compounds and antioxidant activity from rosemary leaf extracts was investigated using high-performance thin-layer chromatography (HPTLC). Brining and spontaneous fermentation with lactic acid bacteria more than doubled extraction of polyphenolics and antioxidants from the rosemary leaves. The results show that lactic acid fermentation enhances antioxidant activity in extracts by increasing the total phenolic content but does not increase extraction of phytosterols. Increased extraction of phenolic oxidants during fermentation assisted extraction, results from the in situ generated natural eutectic solvent from the plant sample. ATR-FTIR spectra from the bioactive bands suggests that this increased antioxidant activity is associated with increased extraction of rosmarinic acid, depolymerised lignin, abietane diterpenoids and 15-hydroxy-7-oxodehydroabietic acid.


Assuntos
Antioxidantes/química , Antioxidantes/metabolismo , Lactobacillales/metabolismo , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Rosmarinus/química , Rosmarinus/metabolismo , Abietanos/química , Abietanos/metabolismo , Cromatografia em Camada Delgada , Cinamatos/química , Cinamatos/metabolismo , Depsídeos/química , Depsídeos/metabolismo , Fermentação , Humanos , Lignina/química , Lignina/metabolismo , Fenóis/química , Fenóis/metabolismo , Folhas de Planta/química , Folhas de Planta/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier
2.
Cell Death Dis ; 12(2): 152, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33542222

RESUMO

Aurora B kinase is aberrantly overexpressed in various tumors and shown to be a promising target for anti-cancer therapy. In human oral squamous cell carcinoma (OSCC), the high protein level of Aurora B is required for maintaining of malignant phenotypes, including in vitro cell growth, colony formation, and in vivo tumor development. By molecular modeling screening of 74 commercially available natural products, we identified that Tanshinone IIA (Tan IIA), as a potential Aurora B kinase inhibitor. The in silico docking study indicates that Tan IIA docks into the ATP-binding pocket of Aurora B, which is further confirmed by in vitro kinase assay, ex vivo pull-down, and ATP competitive binding assay. Tan IIA exhibited a significant anti-tumor effect on OSCC cells both in vitro and in vivo, including reduction of Aurora B and histone H3 phosphorylation, induction of G2/M cell cycle arrest, increase the population of polyploid cells, and promotion of apoptosis. The in vivo mouse model revealed that Tan IIA delayed tumor growth of OSCC cells. Tan IIA alone or in combination with radiation overcame radioresistance in OSCC xenograft tumors. Taken together, our data indicate that Tan IIA is an Aurora B kinase inhibitor with therapeutic potentials for cancer treatment.


Assuntos
Abietanos/farmacologia , Aurora Quinase B/antagonistas & inibidores , Neoplasias Bucais/radioterapia , Inibidores de Proteínas Quinases/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Abietanos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Aurora Quinase B/genética , Aurora Quinase B/metabolismo , Sítios de Ligação , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos da radiação , Humanos , Camundongos Nus , Simulação de Acoplamento Molecular , Neoplasias Bucais/enzimologia , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Ligação Proteica , Inibidores de Proteínas Quinases/metabolismo , Radiossensibilizantes/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/enzimologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Food Funct ; 12(4): 1558-1568, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33459742

RESUMO

As a phenolic terpenoid, carnosic acid (CA) mainly exists in rosemary, which can be effectively used for the treatment of degenerative and chronic diseases by taking advantage of its health-promoting bioactivities. However, the low solubility and dissolution of CA in aqueous solutions at ambient and body temperatures result in low stability and bioaccessibility during the digestion process, which limits its application scope in the functional foods industry. In this regard, a lecithin based nanoemulsion system (CA-NE) is employed in the present work to enhance the bioaccessibility and bioactivities of CA. It is revealed that the CA-NE under investigation exhibits high loading capacity (2.80 ± 0.15%), small particle size (172.0 ± 3.5 nm) with homogeneous particle distribution (polydispersity index (PDI) of 0.231± 0.025) and high repulsive force (zeta potential = -57.2 ± 0.24 mV). More importantly, the bioaccessibility of CA-NE is improved by 2.8-fold compared to that of CA in MCT oil. In addition, the cellular antioxidant assay (CAA) and cellular uptake study of the CA-NE in HepG2 cell models demonstrate a longer endocytosis process, suggesting the well-controlled release of CA from CA-NE. Furthermore, an improved anti-inflammatory activity was evaluated via the inhibition of the pro-inflammatory cytokines, nitric oxide (NO) and TNF-α production in LPS-stimulated RAW 264.7 macrophage cells. The results clearly demonstrated a promising application of CA-NE as a functional food.


Assuntos
Abietanos , Sistemas de Liberação de Medicamentos , Emulsões/química , Lecitinas/química , Nanopartículas/química , Abietanos/química , Abietanos/metabolismo , Abietanos/farmacocinética , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacocinética , Composição de Medicamentos , Células Hep G2 , Humanos , Camundongos , Tamanho da Partícula , Células RAW 264.7
4.
Bioorg Chem ; 106: 104433, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33213893

RESUMO

The G-quadruplex (G4) DNA, which has been developed as a potential anticancer target in drug screening and design, plays a crucial role in the oncogene transcription and translation. Tanshinone IIA derivatives with a planar heterocycle structure may function as G4 stabilizers. We present an innovative case of imidazole-based tanshinone IIA derivatives (1-8) especially compound 4 that improve the selectivity and the binding affinity with G4 DNA and enhance the target tumor inhibition. Cellular and in vivo experiments indicate that the tanshinone IIA derivative 4 inhibits the growth, metastasis, and angiogenesis of triple-negative breast cancer cells possibly through the stabilization of multiple G4 DNAs (e.g., c-myc, K-ras, and VEGF) to induce DNA damage. Further investigation of the intermolecular interaction and the molecular docking indicates that tanshinone IIA derivatives have better selective binding capability to various G4 DNAs than to double-stranded DNA. These findings provide guidance in modifying the molecular structures of tanshinone IIA derivatives and reveal their potential to function as specific G4 stabilizers.


Assuntos
Abietanos/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , DNA/efeitos dos fármacos , Quadruplex G/efeitos dos fármacos , Imidazóis/uso terapêutico , Abietanos/síntese química , Abietanos/metabolismo , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/metabolismo , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , DNA/genética , DNA/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidazóis/síntese química , Imidazóis/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Metástase Neoplásica/prevenção & controle , Regiões Promotoras Genéticas , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Relação Estrutura-Atividade , Peixe-Zebra
5.
Mol Med Rep ; 22(6): 5053-5068, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33174043

RESUMO

Sensorineural hearing loss is prevalent in patients receiving cisplatin therapy. Tetramethylpyrazine (Tet) and tanshinone IIA (Tan IIA) have protective roles against hearing impairment or ototoxicity. The present study aimed to investigate the molecular mechanisms underlying cisplatin­induced ototoxicity and the protective effect of Tet and Tan IIA against it. House Ear Institute­Organ of Corti 1 auditory cells were treated with titrating doses of Tan IIA, Tet, and cisplatin. In a cell viability assay, cisplatin, Tan IIA and Tet had IC50 values of 42.89 µM, 151.80 and 1.04x103 mg/l, respectively. Tan IIA augmented cisplatin­induced cytotoxicity. However, Tet concentrations <75 mg/l attenuated cisplatin­induced cytotoxicity and apoptosis. Moreover, RNA sequencing analysis was carried out on auditory cells treated for 30 h with 30 µM cisplatin alone for 48 h or combined with 37.5 mg/l Tet for 30 h. Differentially expressed genes (DEGs) induced in these conditions were identified and examined using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Cisplatin increased the expression of genes related to the p53 and FoxO pathways, such as Fas, p21/CDKN1A, and Bcl­2 binding component 3, but decreased the expression of insulin­like growth factor 1 (IGF1), as well as genes in the histone (Hist)1 and Hist2 clusters. Treatment with Tet downregulated FOXO3 and Bcl­2 binding component 3, and increased the expression of IGF1. Moreover, Tet upregulated genes associated with Wnt signaling, but not p53­related genes. Thus, the otoprotective properties of Tet might be mediated by activation of Wnt and IGF1 signaling, and inhibition of FoxO signaling.


Assuntos
Abietanos/farmacologia , Perda Auditiva Neurossensorial/metabolismo , Pirazinas/farmacologia , Abietanos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , China , Cisplatino/efeitos adversos , Cisplatino/farmacologia , Bases de Dados Genéticas , Perfilação da Expressão Gênica/métodos , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/prevenção & controle , Humanos , Camundongos , Ototoxicidade , Pirazinas/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
Sci Rep ; 10(1): 19524, 2020 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-33177654

RESUMO

Salvia miltiorrhiza has numerous compounds with extensive clinical application. "Sweating", a processing method of Traditional Chinese Medicine (TCM), results in great changes in pharmacology and pharmacodynamics. Previously, chromatogram of 10 characteristic metabolites in S. miltiorrhiza showed a significant difference after "Sweating". Due to the complexity of TCM, changes in metabolites should be investigated metabolome-wide after "Sweating". An untargeted UPLC/MS-based metabolomics was performed to discover metabolites profile variation of S. miltiorrhiza after "Sweating". Multivariate analysis was conducted to screen differential metabolites. Analysis indicated distinct differences between sweated and non-sweated samples. 10,108 substance peaks had been detected altogether, and 4759 metabolites had been identified from negative and positive ion model. 287 differential metabolites were screened including 112 up-regulated and 175 down-regulated and they belong to lipids and lipid-like molecules, and phenylpropanoid and polyketides. KEGG analysis showed the pathway of linoleic acid metabolism, and glyoxylate and dicarboxylate metabolism were mainly enriched. 31 and 49 identified metabolites were exclusively detected in SSM and NSSM, respectively, which mainly belong to carboxylic acids and derivatives, polyketides and fatty acyls. By mapping tanshinones and salvianolic acids to 4759 identified metabolites library, 23 characteristic metabolites had been identified, among which 11 metabolites changed most. We conclude that "Sweating'' has significant effect on metabolites content and composition of S. miltiorrhiza.


Assuntos
Medicamentos de Ervas Chinesas/metabolismo , Medicina Tradicional Chinesa/métodos , Salvia miltiorrhiza/química , Salvia miltiorrhiza/metabolismo , Abietanos/metabolismo , Alcenos/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/química , Metabolômica/métodos , Análise Multivariada , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Polifenóis/metabolismo , Espectrometria de Massas por Ionização por Electrospray/métodos
7.
Plant Cell Rep ; 39(10): 1263-1283, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32607753

RESUMO

KEY MESSAGE: MIR396b had been cloned and overexpressed in Salvia miltiorrhiza hairy roots. MiR396b targets SmGRFs, SmHDT1, and SmMYB37/4 to regulate cell growth and secondary metabolism in S. miltiorrhiza hairy roots. Danshen (Salvia miltiorrhiza Bunge) is a valuable medicinal herb with two kinds of clinically used natural products, salvianolic acids and tanshinones. miR396 is a conserved microRNA and plays extensive roles in plants. However, it is still unclear how miR396 works in S. miltiorrhiza. In this study, an smi-MIR396b has been cloned from S. miltiorrhiza. Overexpression of miR396b in danshen hairy roots inhibited hairy root growth, reduced salvianolic acid concentration, but enhanced tanshinone accumulation, resulting in the biomass and total salvianolic acids respectively reduced to 55.5 and 72.1% of the control and total tanshinones increased up to 1.91-fold of the control. Applied degradome sequencing, 5'RLM-RACE, and qRT-PCR, 13 targets for miR396b were identified including seven conserved SmGRF1-7 and six novel ones. Comparative transcriptomics and microRNomics analysis together with qRT-PCR results confirmed that miR396b targets SmGRFs, SmHDT1, and SmMYB37/4 to mediate the phytohormone, especially gibberellin signaling pathways and consequentially resulted in the phenotype variation of miR396b-OE hairy roots. Furthermore, miR396b could be activated by methyl jasmonate, abscisic acid, gibberellin, salt, and drought stresses. The findings in this study indicated that smi-miR396b acts as an upstream and central regulator in cell growth and the biosynthesis of tanshinones and salvianolic acids, shedding light on the coordinated regulation of plant growth and biosynthesis of active ingredients in S. miltiorrhiza.


Assuntos
MicroRNAs/metabolismo , Proteínas de Plantas/genética , Raízes de Plantas/citologia , Raízes de Plantas/genética , Salvia miltiorrhiza/citologia , Salvia miltiorrhiza/genética , Abietanos/metabolismo , Ácido Abscísico/farmacologia , Acetatos/farmacologia , Alcenos/metabolismo , Antocianinas/metabolismo , Sítios de Ligação , Biomassa , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Ciclopentanos/farmacologia , Secas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Ontologia Genética , Redes Reguladoras de Genes/efeitos dos fármacos , Giberelinas/farmacologia , MicroRNAs/genética , Oxilipinas/farmacologia , Filogenia , Proteínas de Plantas/metabolismo , Raízes de Plantas/anatomia & histologia , Raízes de Plantas/crescimento & desenvolvimento , Plantas Geneticamente Modificadas , Polifenóis/metabolismo , Propanóis/metabolismo , Estabilidade de RNA/genética , Estresse Salino/efeitos dos fármacos , Estresse Salino/genética , Salvia miltiorrhiza/efeitos dos fármacos , Metabolismo Secundário/efeitos dos fármacos , Terpenos/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Genética/efeitos dos fármacos , Transcriptoma/genética
8.
Poult Sci ; 99(6): 3280-3285, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32475463

RESUMO

Defeathering with rosin results in rosin residue in duck skin, which may present as potential risk to human health. Dehydroabietic acid (DHAA) is a major component of rosin. An indirect competitive enzyme-linked immunosorbent assay (ELISA) was developed for determination of DHAA in duck skin. A set of parameters was optimized, including coating antigen concentration, dilution of antiserum, dilution of HRP-IgG antibody, incubation time, and temperature for antigen reaction with antiserum. The indirect competitive ELISA yielded an excellent specificity against DHAA with low cross-reactivity toward other resin acids. The limit of detection and the working concentration range of DHAA in duck skin were 16.4 ng/g and from 40 to 8,060 ng/g, respectively. The indirect competitive ELISA was applied to the determination of DHAA in duck skin samples spiked with DHAA at different contents, and recoveries were found between 78.2 and 97.2%. Finally, DHAA contents in 32 duck samples were quantified by the indirect competitive ELISA and high performance liquid chromatography-fluorescence detector (HPLC-FLD) method. No significant difference was found between DHAA concentrations from indirect competitive ELISA and HPLC-FLD method for all samples, which indicated the indirect competitive ELISA established in this article was of the same accuracy as the HPLC-FLD method. The indirect competitive ELISA was simple, rapid, and reliable, which could be used to identify the duck carcasses defeathered with rosin in the market.


Assuntos
Abietanos/metabolismo , Cromatografia Líquida de Alta Pressão/veterinária , Patos/metabolismo , Pele/química , Animais , Cromatografia Líquida de Alta Pressão/métodos , Ensaio de Imunoadsorção Enzimática/métodos , Ensaio de Imunoadsorção Enzimática/veterinária , Pele/metabolismo
9.
Genes (Basel) ; 11(5)2020 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-32429385

RESUMO

S. miltiorrhiza is a well-known Chinese herb for the clinical treatment of cardiovascular and cerebrovascular diseases. Tanshinones and phenolic acids are the major secondary metabolites and significant pharmacological constituents of this plant. Kelch repeat F-box (KFB) proteins play important roles in plant secondary metabolism, but their regulation mechanism in S. miltiorrhiza has not been characterized. In this study, we systematically characterized the S. miltiorrhiza KFB gene family. In total, 31 SmKFB genes were isolated from S. miltiorrhiza. Phylogenetic analysis of those SmKFBs indicated that 31 SmKFBs can be divided into four groups. Thereinto, five SmKFBs (SmKFB1, 2, 3, 5, and 28) shared high homology with other plant KFBs which have been described to be regulators of secondary metabolism. The expression profile of SmKFBs under methyl jasmonate (MeJA) treatment deciphered that six SmKFBs (SmKFB1, 2, 5, 6, 11, and 15) were significantly downregulated, and two SmKFBs (SmKFB22 and 31) were significantly upregulated. Tissue-specific expression analysis found that four SmKFBs (SmKFB4, 11, 16, and 17) were expressed preferentially in aerial tissues, while two SmKFBs (SmKFB5, 25) were predominantly expressed in roots. Through a systematic analysis, we speculated that SmKFB1, 2, and 5 are potentially involved in phenolic acids biosynthesis.


Assuntos
Proteínas F-Box/genética , Hidroxibenzoatos/metabolismo , Repetição Kelch/genética , Salvia miltiorrhiza/genética , Abietanos/metabolismo , Abietanos/uso terapêutico , Acetatos/metabolismo , Acetatos/farmacologia , Ciclopentanos/metabolismo , Ciclopentanos/farmacologia , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Oxilipinas/metabolismo , Oxilipinas/farmacologia , Filogenia , Raízes de Plantas/metabolismo , Salvia miltiorrhiza/química , Fatores de Transcrição/genética
10.
Ecotoxicol Environ Saf ; 192: 110311, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32061988

RESUMO

The uptake and accumulation of cadmium (Cd) in Salvia miltiorrhiza (Bge.) negatively affects the quality of its harvested roots, and seriously threatens human health. This study investigates the effect of a microbial inoculant (MI) and garbage enzyme (GE) on Cd uptake, the accumulation of bioactive compounds, and the community composition of microbes in the rhizosphere soil of S. miltiorrhiza under Cd stress. S. miltiorrhiza seedlings were transplanted to Cd-contaminated pots and irrigated with an MI, GE, a combination of an MI and GE (MIGE) or water (control). The results indicated that treatments with an MI, GE or MIGE can reduce Cd uptake in S. miltiorrhiza. The MIGE treatment had greater efficiency in reducing Cd uptake than the control (reduction by 37.90%), followed by the GE (25.31%) and MI (5.84%) treatments. Treatments with an MI, GE and MIGE had no significant impact on fresh and dry root biomass. Relative to the control, the MI treatment had the highest efficiency in increasing the accumulation of total tanshinones (an increase of 40.45%), followed by the GE treatment (40.08%), with the MIGE treatment (9.90%) treatment not having a more favorable effect than the separate application of an MI or GE. The salvianolic acid content for all groups was higher than the standard prescribed by Chinese pharmacopoeia, notwithstanding a slightly lower level in the treated groups relative to the control. In addition, metagenomic analysis indicated changes in the relative abundance of soil microbes associated with the bioremediation of heavy metals. The relative abundances of Brevundimonas, Microbacterium, Cupriavidus and Aspergillus were significantly greater in the treated groups than in the Control. These results suggest that using MI and GE, either separately or together, may not only improve the quality of S. miltiorrhiza but may also facilitate the microbial remediation of soil contaminated with Cd.


Assuntos
Cádmio/toxicidade , Salvia miltiorrhiza/efeitos dos fármacos , Salvia miltiorrhiza/metabolismo , Poluentes do Solo/toxicidade , Abietanos/metabolismo , Alcenos/análise , Biodegradação Ambiental , Biomassa , Cádmio/farmacocinética , Raízes de Plantas/efeitos dos fármacos , Polifenóis/análise , Rizosfera , Salvia miltiorrhiza/química , Microbiologia do Solo
11.
Nat Commun ; 11(1): 971, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080175

RESUMO

Triptolide is a trace natural product of Tripterygium wilfordii. It has antitumor activities, particularly against pancreatic cancer cells. Identification of genes and elucidation of the biosynthetic pathway leading to triptolide are the prerequisite for heterologous bioproduction. Here, we report a reference-grade genome of T. wilfordii with a contig N50 of 4.36 Mb. We show that copy numbers of triptolide biosynthetic pathway genes are impacted by a recent whole-genome triplication event. We further integrate genomic, transcriptomic, and metabolomic data to map a gene-to-metabolite network. This leads to the identification of a cytochrome P450 (CYP728B70) that can catalyze oxidation of a methyl to the acid moiety of dehydroabietic acid in triptolide biosynthesis. We think the genomic resource and the candidate genes reported here set the foundation to fully reveal triptolide biosynthetic pathway and consequently the heterologous bioproduction.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Diterpenos/metabolismo , Fenantrenos/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Tripterygium/genética , Tripterygium/metabolismo , Abietanos/metabolismo , Antineoplásicos Fitogênicos/biossíntese , Vias Biossintéticas/genética , Medicamentos de Ervas Chinesas/metabolismo , Compostos de Epóxi/metabolismo , Perfilação da Expressão Gênica , Genoma de Planta , Humanos , Engenharia Metabólica , Metaboloma , Oxirredução , Filogenia , Plantas Medicinais/genética , Plantas Medicinais/metabolismo
12.
Phytochemistry ; 169: 112183, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31704239

RESUMO

Phenolic acids and tanshinones are the two groups of pharmaceutically active metabolites in Salvia miltiorrhiza Bunge. Their contents are the key quality indicator to evaluate S. miltiorrhiza. bHLH transcription factors have important roles in regulation of plant specialised metabolism. In this study, an endogenous bHLH transcription factor, SmbHLH3, was identified and functionally analyzed. SmbHLH3 was presented in all the six tissues and mostly expressed in fibrous roots and flowers. It was localized to the nucleus. Overexpression of SmbHLH3 decreased both phenolic acids and tanshinones contents. Contents of caffeic acid and rosmarinic acid were both decreased to 50% of the control. And accumulation of salvianolic acid B was decreased as much as 62%. Content of cryptotanshinone, dihydrotanshinone I, tanshinone I and tanshinone IIA in SmbHLH3-overexpression lines were reduced 97%, 62%, 86% and 91%, respectively. In the transgenic lines, expression of C4H1, TAT and HPPR in phenolic acids pathways were reduced to about 43%, 66% and 77% of the control, respectively. For tanshinone biosynthetic pathways, transcripts of DXS3, DXR, HMGR1, KSL1, CPS1 and CYP76AH1 were reduced to 46%, 65%, 78%, 57%, 27% and 62% of the control, respectively. There was an E/G-box specific binding site in SmbHLH3, which may bind the E/G-box present in promoter region of these biosynthetic pathway genes. Y1H results indicated that SmbHLH3 could bind the promoter of TAT, HPPR, KSL1 and CYP76AH1. These findings indicated that SmbHLH3 downregulate both phenolic acids and tanshinone accumulation through directly suppressing the transcription of key enzyme genes.


Assuntos
Abietanos/metabolismo , Hidroxibenzoatos/metabolismo , Raízes de Plantas/metabolismo , Salvia miltiorrhiza/metabolismo , Fatores de Transcrição/metabolismo , Abietanos/química , Regulação para Baixo , Hidroxibenzoatos/química , Estrutura Molecular , Raízes de Plantas/química , Salvia miltiorrhiza/química , Fatores de Transcrição/química , Fatores de Transcrição/genética
13.
J Chromatogr A ; 1614: 460704, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31753480

RESUMO

Profiling the spatial distributions and dynamic changes of metabolites in plant tissue is critical to elucidate the complex metabolic regulation during plant growth, development, and responses to abiotic or biotic stresses. In this study, we developed a high-coverage MALDI-MS imaging method to visualize the spatial locations of a wide spectrum of metabolites in Salvia miltiorrhiza Bge. 1,5-Diaminonaphthalene (DAN) and 1,1'-binaphthyl-2,2'-diamine (BNDM) were optimized as MALDI matrices in positive and negative ion modes respectively, due to their low background interference and high sensitivity. Moreover, a simple organic washing protocol using acetone was shown to significantly improve the sensitivity of MALDI-MSI. Using this method, we successfully imaged the spatial locations of amino acids, phenolic acids, fatty acids, oligosaccharides, cholines, polyamines, tanshinones, and phospholipids in Salvia miltiorrhiza Bge. In addition, the distributions of some metabolites in Salvia miltiorrhiza Bge root and stem were found to exhibit good spatial match with plant tissue structure. Thus, our method provides a spatially-resolved way to map the plant metabolic networks and to understand the physiological roles of several plant metabolites.


Assuntos
Salvia miltiorrhiza/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Abietanos/metabolismo , Aminoácidos/metabolismo , Hidroxibenzoatos/metabolismo , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Caules de Planta/metabolismo , Salvia miltiorrhiza/química
14.
Org Lett ; 22(1): 126-129, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31829019

RESUMO

Leaves of Leucosceptrum canum harbor abundant toxic aromatic abietanoids, and they are rarely attacked by insect herbivores, except for the larvae of Nacna malachitis. The excrements of the insect that fed on L. canum leaves were investigated, leading to the isolation and identification of two unprecedented 11,12-seco-abietane diterpene polyenes: nacnabietanins A (1) and B (2). This discovery heralds a unique detoxification mechanism of plant aromatic abietanoids by insects through enzymatic cleavage of stable benzene rings into more easily degraded polyenes.


Assuntos
Abietanos/metabolismo , Diterpenos/metabolismo , Lamiaceae/química , Polienos/metabolismo , Spodoptera/metabolismo , Abietanos/química , Abietanos/isolamento & purificação , Animais , Diterpenos/química , Lamiaceae/metabolismo , Estrutura Molecular , Folhas de Planta/química , Polienos/química , Spodoptera/química
15.
Appl Biochem Biotechnol ; 191(2): 482-495, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31797151

RESUMO

Biosynthesis of carnosic acid (CA), one of the most industrially valuable medicinal compounds present in rosemary (Rosmarinus officinalis L.) leaves, is affected by various plant stressors. In this study, effects of silver nanoparticle (AgNP) treatment on the secondary metabolism and CA production of rosemary plants were investigated. AgNP of 0, 25, 50, 100, and 200 ppm were utilized on hydroponically grown plants using foliar spray. Efficient absorbance and translocation of AgNPs to the plant roots were confirmed by XRF (X-ray fluorescence) analysis. The fluctuations of important antioxidant compounds such as CA content, phenolics, flavonoids, and acid ascorbic were analyzed and their correlations evaluated. Results revealed that application of 200 ppm AgNPs for 12 days increased CA level more than 11%, as compared to the control plants. Furthermore, significant positive correlations were observed between total flavonoids and CA content under AgNP treatment, suggesting that AgNP acted as an elicitor and triggered the enhancement of CA accumulation effectively. These data suggest that concentration-dependent AgNP may be used to boost antioxidant activity and phytochemical contents of other medicinal plants.


Assuntos
Abietanos/metabolismo , Nanopartículas Metálicas/química , Rosmarinus/efeitos dos fármacos , Rosmarinus/metabolismo , Prata/farmacologia , Antioxidantes/farmacologia , Ácido Ascórbico , Flavonoides/análise , Irã (Geográfico) , Fenóis/metabolismo , Compostos Fitoquímicos/análise , Extratos Vegetais/química , Folhas de Planta/química , Raízes de Plantas/química , Rosmarinus/química
16.
Med Sci Monit ; 25: 7864-7871, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31631173

RESUMO

BACKGROUND Lung cancer is one of the leading causes of cancer-related mortalities worldwide and majority of these deaths result from non-small cell lung cancer (NSCLC). The primary objective of this research was to determine the anticancer potential of carnosic acid, a plant derived abietane diterpene, against human lung cancer cells, as well as to determine its effects on cell migration and invasion, apoptosis, and the PI3K/AKT/m-TOR signaling pathway. MATERIAL AND METHODS Cell viability was evaluated by Cell Counting Kit-8 (CCK-8) assay; fluorescence microscopy using acridine orange/ethidium bromide stain and Comet assay were used to study cellular apoptosis. In vitro wound healing assay was used to study effects on cell migration; Transwell assay was used to study cell invasion after drug treatment. Western blot assay was used to study effects of carnosic acid on the PI3K/AKT/m-TOR signaling pathway. RESULTS It was shown that carnosic acid could inhibit the growth of A-549 human non-small cell lung carcinoma cells dose-dependently showing an IC50 value of 12.5 µM. This growth inhibition of A-549 cells was mediated via apoptotic cell death as observed by fluorescence microscopy showing nuclear fragmentation and chromatin condensation. Carnosic acid, dose-dependently, also inhibited cell migration and invasion. Finally, western blot assay revealed that carnosic acid also led to inhibition of the PI3K/AKT/m-TOR signaling pathway. CONCLUSIONS In conclusion, our results showed that Carnosic acid has the potential to inhibit cancer cell growth in A-549 lung cancer cells by activating apoptotic death, inhibiting cell migration and invasion and suppressing PI3K/AKT/m-TOR signaling pathway.


Assuntos
Abietanos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Células A549 , Abietanos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , China , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Invasividade Neoplásica/fisiopatologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
17.
Biomolecules ; 9(9)2019 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-31455038

RESUMO

Trichoderma atroviride develops a symbiont relationship with Salvia miltiorrhiza and this association involves a number of signaling pathways and proteomic responses between both partners. In our previous study, we have reported that polysaccharide fraction (PSF) of T. atroviride could promote tanshinones accumulation in S. miltiorrhiza hairy roots. Consequently, the present data elucidates the broad proteomics changes under treatment of PSF. Furthermore, we reported several previously undescribed and unexpected responses, containing gene expression patterns consistent with biochemical stresses and metabolic patterns inside the host. In summary, the PSF-induced tanshinones accumulation in S. miltiorrhiza hairy roots may be closely related to Ca2+ triggering, peroxide reaction, protein phosphorylation, and jasmonic acid (JA) signal transduction, leading to an increase in leucine-rich repeat (LRR) protein synthesis. This results in the changes in basic metabolic flux of sugars, amino acids, and protein synthesis, along with signal defense reactions. The results reported here increase our understanding of the interaction between T. atroviride and S. miltiorrhiza and specifically confirm the proteomic responses underlying the activities of PSF.


Assuntos
Abietanos/metabolismo , Polissacarídeos/farmacologia , Proteoma/efeitos dos fármacos , Salvia miltiorrhiza/metabolismo , Trichoderma/metabolismo , Cromatografia Líquida de Alta Pressão , Ciclopentanos/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Espectrometria de Massas , Oxilipinas/farmacologia , Fosforilação/efeitos dos fármacos , Proteínas de Plantas/metabolismo , Raízes de Plantas/metabolismo , Polissacarídeos/análise , Polissacarídeos/isolamento & purificação , Proteoma/análise , Proteoma/metabolismo , Transdução de Sinais/efeitos dos fármacos
18.
J Food Biochem ; 43(7): e12851, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31353697

RESUMO

Rosemary ethanol extract (REE) from Rosmarinus officinalis was identified by LC-ESI-MS/MS and 12 compounds were found. Among them, rosmarinic acid (389.78 µg/mg in REE), luteolin-3'-O-glucuronide (325.58 µg/mg), luteolin-5-O-glucuronide (120.92 µg/mg), and geniposide (120.83 µg/mg) are the major components. The antioxidant activity evaluation of REE by off-line HPLC methods indicated that among the 12 compounds, rosmarinic acid had the strongest scavenging activities in both DPPH· and ·OH. The cytotoxicity experiment showed that REE with the concentration ranges from 1 to 100 µg/ml did not significantly affect the cell viability of HeLa, while inhibitory rate reduced to 62.3% when the concentration was increased to 1,000 µg/ml. The results of intracellular antioxidation assay showed that the ability of REE in reducing the reactive oxygen species (ROS) in HeLa cells was higher than rosmanol, and lower than rosmarinic acid without cell toxicity. PRACTICAL APPLICATIONS: Plant polyphenols are essential components of functional foods, due to their antioxidant and enzyme inhibition activities. This paper is the first study about the quantification of antioxidant compounds, antioxidant activity evaluation, and their cellular antioxidant activity of polyphenols extract from R. officinalis toward HeLa cells. We aimed to elucidate the chemical composition and recognition of antioxidant components with DPPH and OH free radicals scavenging activity. In addition, the polyphenols dose-response correlations with cellular antioxidant activity were also determined. These results indicated that off-line HPLC method with DPPH and OH free radicals as markers is available for screening antioxidant activity of polyphenols from the mixture.


Assuntos
Antioxidantes , Extratos Vegetais , Polifenóis , Rosmarinus/química , Abietanos/metabolismo , Abietanos/toxicidade , Antioxidantes/análise , Antioxidantes/farmacologia , Antioxidantes/toxicidade , Cromatografia Líquida de Alta Pressão , Cinamatos/metabolismo , Cinamatos/toxicidade , Depsídeos/metabolismo , Depsídeos/toxicidade , Etanol , Sequestradores de Radicais Livres , Células HeLa , Humanos , Extratos Vegetais/análise , Extratos Vegetais/farmacologia , Extratos Vegetais/toxicidade , Folhas de Planta/química , Polifenóis/análise , Polifenóis/farmacologia , Polifenóis/toxicidade , Espécies Reativas de Oxigênio/metabolismo
19.
Med Sci Monit ; 25: 4793-4800, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31250836

RESUMO

BACKGROUND The aim of this study was to explore the effect and mechanism of tanshinone II A on proliferation, apoptosis, and migration of human colon cancer cells. MATERIAL AND METHODS CCK-8 approach was carried out to evaluate proliferation after applying various levels of tanshinone II A to SW620 colon carcinoma cells. Flow cytometry (FC) was used to assess apoptosis. Transwell assay was performed to assess invasion in vitro, and the wound-healing assay was applied to assess migration. Western blot analysis was performed to evaluate translation of mTOR, while RT-PCR was carried out to assess transcription of VEGF. RESULTS CCK-8 assay showed that tanshinone II A inhibited SW620 proliferation in comparison to the control group subsequent to 24 h, 48 h, and 72 h (P<0.001). FC revealed that tanshinone II A promoted SW620 apoptosis (P<0.001). The cell migration test revealed that the migration index of cells receiving tanshinone II A decreased. mTOR translation as well as VEGE transcription in cells receiving tanshinone II A was noticeably prohibited compared to control group (P<0.001). CONCLUSIONS Tanshinone II A is able to inhibit proliferation and migration of human colon cancer SW620 cells and promoted cell death. Its mechanism may be by downregulation of mTOR protein and VEGF mRNA.


Assuntos
Abietanos/farmacologia , Neoplasias do Colo/metabolismo , Abietanos/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Humanos , Transdução de Sinais/efeitos dos fármacos
20.
Pharm Dev Technol ; 24(8): 982-991, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31107131

RESUMO

Tanshinone I (TSI) is one of the bioactive compound obtained from the root of Salvia miltiorrhiza which is a well-known traditional Chinese medicine (TCM) used for the treatment of various diseases. Although TSI possesses several pharmacological effects, it has poor water solubility, blood-brain barrier (BBB) permeability and brain bioavailability. Therefore, in the present study, we developed TSI nanoemulsion (TSI-NE) modified with a brain targeting ligand (Lactoferrin (Lf)) to improve the BBB permeability. Pseudo-ternary phase diagrams were used to optimize the formulation. The optimal TSI-NE and TSI-Lf-NE were prepared and characterized. Finally, the uptake of TSI-Lf-NE by mouse brain microvascular endothelial cell line (bEnd.3 cells) was assessed using Coumarin-6 as a fluorescent probe. The results of the study showed that the stable optimal formulation of O/W nanoemulsion was successfully developed and modified with Lf. The cellular uptake study has shown that the fluorescence intensity (FI) increased with time over the incubation period. The FI at all time intervals increased in the following order: Coumarin-6-Solution<Coumarin-6-NE<Coumarin-6-Lf-NE. The results suggest that the BBB permeability of Coumarin-6-Lf-NE was better than those of Coumarin-6-NE and Coumarin-6 solution. Lf modified nanoemulsion has great potential for improving the brain delivery of TSI.


Assuntos
Abietanos/química , Abietanos/metabolismo , Encéfalo/metabolismo , Emulsões/química , Lactoferrina/química , Nanopartículas/química , Animais , Disponibilidade Biológica , Transporte Biológico/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Cumarínicos/química , Cumarínicos/metabolismo , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Emulsões/metabolismo , Lactoferrina/metabolismo , Camundongos , Nanopartículas/metabolismo , Tamanho da Partícula , Permeabilidade/efeitos dos fármacos , Polietilenoglicóis/química , Solubilidade , Tiazóis/química , Tiazóis/metabolismo , Distribuição Tecidual/efeitos dos fármacos
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