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1.
Lett Appl Microbiol ; 76(1)2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36688762

RESUMO

To improve the conversion efficiency of rebaudioside C, this study screened the Paenarthrobacter ilicis CR5301 from soil samples and identified it by 16S rRNA. The conversion experiment proved that P. ilicis CR5301 was capable of converting rebaudioside C. The effects of initial pH, temperature, inoculation amount, and substrate concentration on rebaudioside C conversion rate were investigated. The results showed that the conversion rate of rebaudioside C reached up to 100% when CR5301 was incubated in a conversion medium with an initial pH of 7.0 for 8 h at 28°C and 270 rpm. The conversion time was reduced by at least 16 h compared with previous studies. The conversion product was analyzed and identified as steviol by high performance liquid chromatography, ultra performance liquid chromatography-triple-time of flight mass spectrometer, and Fourier transform infrared spectroscopy methods. In addition, stevioside, rebaudioside A, dulcoside A, and some unknown components in steviol glycosides byproduct were all efficiently converted to steviol. These findings provide an efficient approach to the conversion of rebaudioside C and byproduct to steviol to simplify the subsequent industrial process and improve the reuse value of steviol glycosides.


Assuntos
Diterpenos do Tipo Caurano , Stevia , RNA Ribossômico 16S , Glucosídeos , Diterpenos do Tipo Caurano/análise , Diterpenos do Tipo Caurano/química , Stevia/química , Glicosídeos/análise
2.
Carbohydr Res ; 523: 108737, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36657220

RESUMO

Steviol glycosides have attracted great interest because of their high levels of sweetness and safety, and absence of calories. Improvement of their sensory qualities via glycosylation modification by glycosyltransferase is a research hotspot. In this study, YjiC, a uridine diphosphate-dependent glycosyltransferase from Bacillus subtilis 168, was found with the ability to glycosylate rebaudioside A (Reb A) to produce a novel mono ß-1, 6-glycosylated Reb A derivative rebaudioside L2 (Reb L2). It has an improved sweetness compared with Reb A. Next, a cascade reaction was established by combining YjiC with sucrose synthase AtSuSy from Arabidopsis thaliana for scale-up preparation of Reb L2. It shows that Reb L2 (30.94 mg/mL) could be efficiently synthesized with an excellent yield of 91.34% within 12 h. Therefore, this study provides a potential approach for the production and application of new steviol glycoside Reb L2, expanding the scope of steviol glycosides.


Assuntos
Diterpenos do Tipo Caurano , Stevia , Glicosiltransferases , Glucosídeos , Catálise
3.
J Am Chem Soc ; 145(1): 311-321, 2023 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-36538760

RESUMO

A unified strategy toward asymmetric divergent syntheses of nine C8-ethano-bridged diterpenoids A1-A9 (candol A, powerol, sicanadiol, epi-candol A, atisirene, ent-atisan-16α-ol, 4-decarboxy-4-methyl-GA12, trachinol, and ent-beyerane) has been developed based on late-stage transformations of common synthons having ent-kaurane and ent-trachylobane cores. The expeditious assembly of crucial advanced ent-kaurane- and ent-trachylobane-type building blocks is strategically explored through a regioselective and diastereoselective Fe-mediated hydrogen atom transfer (HAT) 6-exo-trig cyclization of the alkene/enone and 3-exo-trig cyclization of the alkene/ketone, showing the multi-reactivity of densely functionalized polycyclic substrates with πC═C and πC═O systems in HAT-initiated reactions. Following the rapid construction of five major structural skeletons (ent-kaurane-, ent-atisane-, ent-beyerane-, ent-trachylobane-, and ent-gibberellane-type), nine C8-ethano-bridged diterpenoids A1-A9 could be accessed in the longest linear 8 to 11 steps starting from readily available chiral γ-cyclogeraniol 1 and known chiral γ-substituted cyclohexenone 2, in which enantioselective total syntheses of candol A (A1, 8 steps), powerol (A2, 9 steps), sicanadiol (A3, 10 steps), epi-candol A (A4, 8 steps), ent-atisan-16α-ol (A6, 11 steps), and trachinol (A8, 10 steps) are achieved for the first time.


Assuntos
Diterpenos do Tipo Caurano , Diterpenos
4.
Molecules ; 27(23)2022 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-36500693

RESUMO

The Nemo's Garden® project is an alternative production system for areas with scarce cultivable land but significant presence of water; thus, it is an interesting intervention to address the climate crisis. This work aimed to evaluate the micromorphological, biochemical, and phytochemical characteristics of Stevia rebaudiana (Bertoni) Bertoni grown underwater compared to the terrestrial specimens. The micromorphological analyses, performed on the leaves using light microscopy, fluorescence microscopy, and scanning electron microscopy, evidenced a general uniformity of the trichome morphotype and distribution pattern. The histochemical investigation indicated the simultaneous presence of terpenes and polyphenols in the trichome secreted material from the underwater samples and a prevailing polyphenolic content in the terrestrial specimens; this was also confirmed by biochemical analyses (26.6 mg GAE/g DW). The characterization of non-volatile components, performed using HPLC-MS, showed similar chemical profiles in all the samples, which were characterized by phenolic compounds and steviol glycosides. The volatile compounds, evaluated using HS-SPME coupled with GC-MS, showed sesquiterpene hydrocarbons as the main class in all the analyzed samples (80.1-93.9%). However, the control plants were characterized by a higher content of monoterpene hydrocarbons (12.1%). The underwater biosphere environment did not alter S. rebaudiana micro-morphological characters, although slight qualitative changes were evidenced for the compounds produced as a response to the growth conditions.


Assuntos
Diterpenos do Tipo Caurano , Stevia , Stevia/química , Diterpenos do Tipo Caurano/análise , Folhas de Planta/química , Polifenóis/química , Cromatografia Líquida de Alta Pressão , Aclimatação
5.
Genes (Basel) ; 13(11)2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36421808

RESUMO

Pyroptosis serves a crucial function in various types of ischemia and reperfusion injuries. Oridonin, a tetracycline diterpene derived from Rabdosia rubescens, can significantly inhibit the aggregation of NLRP3-mediated inflammasome. This experiment is aimed at investigating the effect of oridonin on pyroptosis in mice cardiomyocytes. Based on the models of myocardial ischemia/reperfusion (I/R) and hypoxia/reoxygenation (H/R), Evans Blue/TTC double staining, TUNEL staining, and Western blotting were applied to determine the effects of oridonin on myocardial damage, cellular activity and signaling pathways involved in pyroptosis. During I/R and H/R treatments, the extent of gasdermin D-N domains was upregulated in cardiomyocytes. Apart from that, oridonin improved cell survival in vitro and decreased the myocardial infarct size in vivo by also downregulating the activation of pyroptosis. Finally, the expression levels of ASC, NLRP3 and p-p65 were markedly upregulated in cardiomyocytes after H/R treatment, whereas oridonin suppressed the expression of these proteins. The present experiment revealed that myocardial I/R injury and pyroptosis can be alleviated and inhibited by oridonin pretreatment via NF-κB/NLRP3 signaling pathway, both in vivo and in vitro. Therefore, oridonin may serve as a potentially novel agent for the clinical treatment of myocardial ischemia-reperfusion injuries.


Assuntos
Diterpenos do Tipo Caurano , Traumatismo por Reperfusão Miocárdica , Piroptose , Animais , Camundongos , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
6.
Chem Pharm Bull (Tokyo) ; 70(12): 901-906, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36450588

RESUMO

From the less polar fraction of the MeOH extract of the leaves and twigs of Omphalea oppositifolia, five new ent-rosane-type diterpenoids, named omphalines A-E (1-5), were isolated together with one known compound, 7-keto-ent-kaurane-16ß,17-diol (6), by a combination of various kinds of chromatography. The structure of omphaline A (1) was elucidated to be 19-nor-ent-rosane-4,15-diene-2ß,6α-diol-3-one. Omphalines B (2), C (3), D (4), and E (5) possessed two double bonds at 5- and 15-positions, and hydroxy functional groups at 3ß-, 2α,3α-, 2α,3ß-, and 2α,19-positions, respectively. The absolute configuration of 1 was determined by the comparison of the experimental electronic circular dichroism (ECD) spectrum and calculated ECD spectra.


Assuntos
Diterpenos do Tipo Caurano , Diterpenos , Euphorbiaceae , Madagáscar , Dicroísmo Circular
7.
Int J Mol Sci ; 23(19)2022 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-36232690

RESUMO

Human nucleolin (hNcl) is a multifunctional protein involved in the progression of various cancers and plays a key role in other pathologies. Therefore, there is still unsatisfied demand for hNcl modulators. Recently, we demonstrated that the plant ent-kaurane diterpene oridonin inhibits hNcl but, unfortunately, this compound is quite toxic for healthy cells. Trachylobane diterpene 6,19-dihydroxy-ent-trachiloban-17-oic acid (compound 12) extracted from Psiadia punctulata (DC.) Vatke (Asteraceae) emerged as a ligand of hNcl from a cellular thermal shift assay (CETSA)-based screening of a small library of diterpenes. Effective interaction between this compound and the protein was demonstrated to occur both in vitro and inside two different types of cancer cells. Based on the experimental and computational data, a model of the hNcl/compound 12 complex was built. Because of this binding, hNcl mRNA chaperone activity was significantly reduced, and the level of phosphorylation of the protein was affected. At the biological level, cancer cell incubation with compound 12 produced a cell cycle block in the subG0/G1 phase and induced early apoptosis, whereas no cytotoxicity towards healthy cells was observed. Overall, these results suggested that 6,19-dihydroxy-ent-trachiloban-17-oic could represent a selective antitumoral agent and a promising lead for designing innovative hNcl inhibitors also usable for therapeutic purposes.


Assuntos
Asteraceae , Diterpenos do Tipo Caurano , Diterpenos , Neoplasias , Asteraceae/química , Diterpenos/química , Diterpenos/farmacologia , Diterpenos do Tipo Caurano/química , Diterpenos do Tipo Caurano/farmacologia , Humanos , Ligantes , Neoplasias/tratamento farmacológico , Fosfoproteínas , Fosforilação , RNA Mensageiro , Proteínas de Ligação a RNA
8.
Food Res Int ; 161: 111899, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36192918

RESUMO

Government regulatory actions and public policies to reduce sugar consumption were recently implemented in Brazil. To evaluate their potential impact on the supply of products containing high-intensity sweeteners (HIS) and on dietary exposure to these substances, this study aimed to create a comprehensive database on HIS declared in Brazilian commercial products and estimate their intake through consumption of these products. The occurrence of HIS was evaluated through labeling information of 1869 commercial products available in the Brazilian market, collected between January 2021 and August 2021, and the daily intake was estimated for eight HIS (acesulfame K, advantame, aspartame, cyclamate, steviol glycosides, neotame, saccharin and sucralose) using a deterministic approach by multiplying the maximum permitted levels of HIS in foods and beverages by the consumption data of these products. The consumption data were obtained from the report of Household Budget Survey (POF/IBGE), conducted from 2017 to 2018 through a 24-hour dietary recall applied to 46,164 individuals aged 10 years and over, which included only average data (i.e. average consumption for the general population or subgroups). The most frequent HIS in the investigated products were sucralose (26.8 %; n = 938) and acesulfame K (21.7 %; n = 759), and although the combination of sweeteners is a common practice in the food industry, there was a predominance of only one substance in the investigated products (46.7 %; n = 873). The estimated intake of HIS for average consumers was below the Acceptable Daily Intake (ADI) and does not suggest a toxicological concern. A similar scenario was observed for high consumers, except for cyclamate and steviol glycosides, which corresponded to 144 % and 131 % of their respective ADIs in the general population. To our knowledge, this is the most comprehensive database on HIS in Brazil and the most recent exposure assessment performed nationally.


Assuntos
Aspartame , Adoçantes não Calóricos , Brasil , Ciclamatos , Açúcares da Dieta , Diterpenos do Tipo Caurano , Glucosídeos , Humanos , Sacarina , Edulcorantes/análise , Tiazinas
9.
Nutrients ; 14(19)2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36235824

RESUMO

Non-nutritive sweeteners have potential effects on brain function. We investigated neural correlates of responses to beverages differing in sweetness and calories. Healthy participants completed 4 randomised sessions: water vs. water with stevia, glucose, or maltodextrin. Blood-oxygenation level-dependent (BOLD) contrast was monitored for 30 min post-ingestion by functional Magnetic Resonance Imaging. A food visual probe task at baseline was repeated at 30 min. A significant interaction of taste-by-calories-by-time was demonstrated mainly in motor, frontal, and insula cortices. Consumption of the stevia-sweetened beverage resulted in greater BOLD decrease, especially in the 20-30 min period, compared to other beverages. There was a significant interaction of taste-by-time in BOLD response in gustatory and reward areas; sweet beverages induced greater reduction in BOLD compared to non-sweet. The interaction calories-by-time showed significantly greater incremental area under the curve in thalamic, visual, frontal, and parietal areas for glucose and maltodextrin 10-20 min post-consumption only, compared to water. In the visual cue task, the water demonstrated an increased response in the visual cortex to food images post-consumption; however, no difference was observed for the three sweet/caloric beverages. In conclusion, both sweet taste and calories exert modulatory effects, but stevia showed a more robust and prolonged effect.


Assuntos
Adoçantes não Calóricos , Stevia , Adulto , Encéfalo , Estudos Cross-Over , Diterpenos do Tipo Caurano , Glucose , Glucosídeos , Humanos , Adoçantes não Calóricos/farmacologia , Edulcorantes/farmacologia , Água
10.
Carbohydr Res ; 522: 108687, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36270051

RESUMO

Steviol glycosides have been widely applied as new sweeteners in food, beverages, health care, and daily chemical industry owing to the properties of high-intensity sweetness, low calorie, and good physiological characteristics. However, most of steviol glycosides have a bitter taste. Their organoleptic properties can be effectively improved by modifying the linked glycosyl units. In this study, UGT94D1, a uridine diphosphate-dependent glycosyltransferase from Sesamum indicum, was reported to selectively glycosylate rebaudioside A (Reb A) for the synthesis of rebaudioside D2 (Reb D2). Furthermore, a cascade reaction system was constructed to synthesize Reb D2 with 94.66% yield by coupling UGT94D1 with sucrose synthase AtSuSy from Arabidopsis thaliana. Thus, our study not only introduced a practical method for the synthesis of steviol glycosides but also provided the possibility for further exploration of Reb D2.


Assuntos
Diterpenos do Tipo Caurano , Stevia , Stevia/química , Glicosilação , Diterpenos do Tipo Caurano/química , Glucosídeos/química , Catálise
11.
Biochem Biophys Res Commun ; 629: 152-158, 2022 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-36122452

RESUMO

Acute myeloid leukemia (AML) is the most common blood cancer in adults. Patients' 5-year overall survival is less than 30% thus having a poor prognosis. To date, the development of novel target therapies is still necessary to ameliorate patients' survival. Antibody-drug conjugates (ADCs) represent a promising class of drugs for the treatment of AML. CD33 is highly expressed on AML cells, and the FDA-approved CD33-targeted ADC drug-gemtuzumab ozogamicin (GO) has proved the feasibility of CD33-targeted ADC drug design. In this study, we constructed a novel CD33-targeted ADC drug composed of a humanized anti-CD33 antibody and oridonin as a payload with a cleaved chemical linker. Oridonin is a natural product that has great cancer therapy potential while its poor bioavailability and targeting ability limited its clinical use. Herein, we demonstrated that antiCD33-oridonin specifically delivered oridonin in AML cells improved AML cells killing ability of oridonin. Meanwhile, it did not show any non-specific toxicity on CD33 negative cells. In summary, we developed a novel AML targeting ADC with clinical application potential, and therefore provided a new solution for the druggability improvement of oridonin.


Assuntos
Produtos Biológicos , Imunoconjugados , Leucemia Mieloide Aguda , Adulto , Aminoglicosídeos , Anticorpos Monoclonais Humanizados/uso terapêutico , Produtos Biológicos/uso terapêutico , Diterpenos do Tipo Caurano , Gemtuzumab , Humanos , Imunoconjugados/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico
12.
Bioorg Chem ; 129: 106142, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36150232

RESUMO

Cardiovascular diseases (CVDs) remain the leading cause of death globally. Inhibiting ferroptosis and thus preventing cardiac cell death is a promising and effective strategy for cardiomyopathy prevention and therapy. Steviol, an ent-kaurene diterpenoid, possesses broad-spectrum bioactivity. In the present study, with the aim to discover new agents for CVDs treatment, 30 derivatives of steviol, including 22 new ones, were synthesized, and evaluated their protective activity in vivo using the doxorubicin (DOX) induced zebrafish cardiomyopathy model. Our results firstly demonstrated that steviol has promising cardioprotective activity and further modification of steviol can greatly improve the activity. Among the new derivatives, 16d and 16e show the most potent activity. Both 16d (1 µM) and 16e (0.1 µM) effectively maintain the normal heart shape and prevent the cardiac dysfunction impaired by DOX in zebrafish. Their therapeutic efficacy is much superior to the parent natural product, steviol, and positive drug, levosimendan. Further study demonstrated that 16d and 16e inhibit DOX-induced ferroptosis and thus protect cardiomyopathy, by suppressing the glutathione depletion, iron accumulation, and lipid peroxidation, decreasing reactive oxygen species overaccumulation, and restoring the mitochondrial membrane potential. Consequently, due to their unique structure and significant cardioprotective activity with ferroptosis inhibition, new steviol derivatives 16d and 16e merit further research for the development of new cardioprotective drug candidates.


Assuntos
Cardiomiopatias , Diterpenos do Tipo Caurano , Ferroptose , Animais , Peixe-Zebra , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/uso terapêutico , Doxorrubicina/farmacologia , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/prevenção & controle
13.
Nutrients ; 14(17)2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36079779

RESUMO

Stevioside, one of the natural sweeteners extracted from stevia leaves, and its derivatives are considered to have numerous beneficial pharmacological properties, including the inhibition of activated coagulation factor X (FXa). FXa-PAR signaling is a possible therapeutic target to enhance impaired metabolism and insulin resistance in obesity. Thus, the goal of the investigation was a QSAR analysis using multivariate adaptive regression splines (MARSplines) applied to a data set of 20 isosteviol derivatives bearing thiourea fragments with possible FXa inhibitory action. The best MARS submodel described a strong correlation between FXa inhibitory activity and molecular descriptors, such as: B01[C-Cl], E2m, L3v, Mor06i, RDF070i and HATS7s. Five out of six descriptors included in the model are geometrical descriptors quantifying three-dimensional aspects of molecular structure, which indicates that the molecular three-dimensional conformation is of high significance for the MARSplines modeling procedure and obviously for FXa inhibitory activity. High model performance was confirmed through an extensive validation protocol. The results of the study not only confirmed the enhancement in pharmacological activity by the presence of chlorine in a phenyl ring, but also, and primarily, may provide the basis for searching for new active isosteviol analogues, which may serve as drugs or health-beneficial food additives in patients suffering from obesity and comorbidities.


Assuntos
Fator X , Relação Quantitativa Estrutura-Atividade , Diterpenos do Tipo Caurano , Humanos , Estrutura Molecular , Obesidade , Relação Estrutura-Atividade
14.
IUBMB Life ; 74(10): 1012-1028, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36054915

RESUMO

Steviol glycosides, the active sweet components of stevia plant, have been recently found to possess a number of therapeutic properties, including some recorded anticancer ones against various cancer cell types (breast, ovarian, cervical, pancreatic, and colon cancer). Our aim was to investigate this anticancer potential on the two most commonly used breast cancer cell lines which differ in the phenotype and estrogen receptor (ER) status: the low metastatic, ERα+ MCF-7 and the highly metastatic, ERα-/ERß+ MDA-MB-231. Specifically, glycosides' effect was studied on cancer cells': (a) viability, (b) functionality (proliferation, migration, and adhesion), and (c) gene expression (mRNA level) of crucial molecules implicated in cancer's pathophysiology. Results showed that steviol glycosides induced cell death in both cell lines, in the first 24 hr, which was in line with the antiapoptotic BCL2 decrease. However, cells that managed to survive showcased diametrically opposite behavior. The low metastatic ERα+ MCF-7 cells acquired an aggressive phenotype, depicted by the upregulation of all receptors and co-receptors (ESR, PGR, AR, GPER1, EGFR, IGF1R, CD44, SDC2, and SDC4), as well as VIM and MMP14. On the contrary, the highly metastatic ERα-/ERß+ MDA-MB-231 cells became less aggressive as pointed out by the respective downregulation of EGFR, IGF1R, CD44, and SDC2. Changes observed in gene expression were compatible with altered cell functions. Glycosides increased MCF-7 cells migration and adhesion, but reduced MDA-MB-231 cells migratory and metastatic potential. In conclusion, the above data clearly demonstrate that steviol glycosides have different effects on breast cancer cells according to their ER status, suggesting that steviol glycosides might be examined for their potential anticancer activity against breast cancer, especially triple negative breast cancer (TNBC).


Assuntos
Receptor alfa de Estrogênio , Neoplasias , Diterpenos do Tipo Caurano , Receptores ErbB , Receptor beta de Estrogênio/fisiologia , Glucosídeos , Glicosídeos/farmacologia , Metaloproteinase 14 da Matriz , Proteínas Proto-Oncogênicas c-bcl-2 , RNA Mensageiro , Receptores de Estrogênio
15.
J Biotechnol ; 358: 76-91, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36075450

RESUMO

Stevia rebaudiana is one of the vastly acclaimed commercial plant in the world and belongs to Asteraceae family. The exclusive advantage of Stevia over artificial sweeteners is impeccable and targets its potentiality to the presence of diterpene glycosides. Moreover, the flaunting sweetness of steviol glycosides with associated medicinal benefits, turns the plant to be one of the most economic assets, globally. As compared to vegetative propagation through stem-cuttings, plant tissue culture is the most suitable approach in obtaining true-to-type plants of superior quality. During last few decades, significant in vitro propagation methods have been developed and still the research is ongoing. The present review discusses the tissue culture perspectives of S. rebaudiana, primarily focusing on the mineral nutrition, growth regulators and other accessory factors, motioning the optimum growth and development of the plant. Another crucial aspect is the generation of sweeter varieties in order to reduce the bitter-off taste, which is noticed after the consumption of the leaves. The in vitro cultures pose an efficient alternative system for production of steviol glycosides, with higher rebaudioside(s) content. Moreover, the review also covers the recent approaches pertaining to scale-up studies and genome editing perspectives.


Assuntos
Diterpenos do Tipo Caurano , Stevia , Glucosídeos , Glicosídeos , Folhas de Planta/genética , Stevia/genética , Edulcorantes
16.
Fitoterapia ; 162: 105296, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36087821

RESUMO

Four new diterpenoids (1-4), and 18 known ones were isolated from the roots of Euphorbia fischeriana Steud (Euphorbiaceae). These diterpenoids shared six skeleton types, including ent-atisane, kaurane, 3,4-secokaurane, lathyrane, 4,5-secoatisane and ingenane diterpenoids. The structures of the new diterpenoids were characterized by a combination of spectroscopic techniques and X-ray crystallography. Moreover, biological evaluation revealed that compounds (16S*)-atisan-3ß,16,17-triol (7), (16S*)-3ß,16,17,18-tetrahydroxykaurane (12) and (16S*)-3α-hydroxykauran-16,17-acetonide (15) showed inhibitory activity against the interferon regulatory factors (IRFs) involved pathway.


Assuntos
Diterpenos do Tipo Caurano , Diterpenos , Euphorbia , Diterpenos/química , Diterpenos/farmacologia , Euphorbia/química , Fatores Reguladores de Interferon/análise , Estrutura Molecular , Raízes de Plantas/química
17.
Biomed Pharmacother ; 153: 113532, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076611

RESUMO

Silicosis, the most common type of pneumoconiosis, exhibits a high incidence in workers who are chronically exposed to crystalline silica (CS). No specific remedy for cure as yet. The terpenoid oridonin exerts multiple modulatory functions in neoplasms and inflammations as a natural compound. In this study, we explored the effect of oridonin on silicosis and revealed the underlying molecular mechanism. An experimental silicosis mouse model was established to evaluate the effects of oridonin on pneumonia and pulmonary fibrosis. In addition, the impact of oridonin on alveolar macrophages (AMs) was examined in the MH-S cell line. Its molecular target, inducible nitric oxide synthase (iNOS), was identified by chemobiological means, and virus-mediated gene overexpression systems confirmed that oridonin directly restrained iNOS protein levels. Oridonin alleviated pneumonia and pulmonary fibrosis in silicosis mice with no obvious systemic toxicity. These effects were partially related to oridonin inhibition of CS-induced AMs injury and inflammation. Furthermore, oridonin suppressed iNOS enzymatic expression and activity by covalently binding to the Thr109 residue of the iNOS target. Thus, our results indicate oridonin as a potential iNOS enzymatic suppressor in experimental silicosis that attenuates pneumonia and pulmonary fibrosis progression, which provides a therapeutic avenue for silicosis prevention and treatment.


Assuntos
Diterpenos do Tipo Caurano , Pneumonia , Fibrose Pulmonar , Silicose , Animais , Diterpenos do Tipo Caurano/farmacologia , Fibrose , Inflamação/metabolismo , Pulmão , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/metabolismo , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Dióxido de Silício/efeitos adversos , Silicose/tratamento farmacológico , Silicose/metabolismo
18.
Fitoterapia ; 163: 105314, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36174847

RESUMO

The ent-kaurane diterpenoid enriched fraction (EDEF) of maize root was isolated and purified, and 10 compounds, including 4 ent-kaurane diterpenoids, were isolated and identified. We evaluated their neuroprotective properties in vitro for the first time using an H2O2-induced oxidative damage model in SH-SY5Y cells. The results showed that pretreatment with maizediterpene D, a new ent-kaurane diterpenoid isolated from the EDEF, significantly attenuated H2O2-induced apoptosis by improving cell survival, reducing ROS production and increasing mitochondrial membrane potential. Mechanistically, the neuroprotective effect of maizediterpene D was confirmed to be related to the dual activation of IGF-1R and BDNF/TrkB crosstalk pathways. Our findings suggest that the EDEF and its active constituent maizediterpene D had good neuroprotective properties and could serve as potential candidates for the development of therapeutic drugs for oxidative stress-related diseases.


Assuntos
Diterpenos do Tipo Caurano , Diterpenos , Neuroblastoma , Fármacos Neuroprotetores , Humanos , Peróxido de Hidrogênio/farmacologia , Zea mays , Sobrevivência Celular , Estrutura Molecular , Estresse Oxidativo , Diterpenos do Tipo Caurano/farmacologia , Fármacos Neuroprotetores/farmacologia , Apoptose , Diterpenos/farmacologia , Linhagem Celular Tumoral
19.
Chem Biodivers ; 19(10): e202200497, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36050280

RESUMO

One new (1) and 11 reported ent-kaurane diterpenoids (2-12) were received from the ethanol extract of the air-dried aerial parts of Rabdosia rubescens collected in Jiyuan. Their structures were determined in accordance with high resolution electrospray ionization mass spectroscopy, one dimensional (1D) and two-dimensional (2D) NMR spectroscopy and the data published in the literature. The cytotoxic activity of these isolated compounds was assessed against SMMC-7721, A-549, H-1299 and SW-480 cancer cell lines. Compounds 2-6 revealed significant cytotoxic activity on lung cancer cell lines A549 with IC50 values from 6.2 to 28.1 µM. Analysis of structure-activity relationship of these tested compounds indicated the carbonyl at C-15 and hydroxy at C-1 together could be crucial groups for inhibiting lung cancer cell lines A549 proliferation.


Assuntos
Antineoplásicos Fitogênicos , Antineoplásicos , Diterpenos do Tipo Caurano , Diterpenos , Isodon , Neoplasias Pulmonares , Humanos , Isodon/química , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/química , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Estrutura Molecular , Antineoplásicos/farmacologia , Extratos Vegetais/química , Neoplasias Pulmonares/tratamento farmacológico , Etanol
20.
Mol Med Rep ; 26(4)2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36004485

RESUMO

Ulcerative colitis (UC) is a serious chronic inflammatory bowel disease. Oridonin (Ori) has anti­inflammatory, antibacterial and antitumor activities. The current study aimed to investigate the regulatory role of Ori in UC. BALB/C mice were induced to form a model of UC using dextran sulfate sodium (DSS), after which UC mice received high­(Ori­H) and low­doses of Ori (Ori­L). Subsequently, the length of the colon was measured and hematoxylin and, eosin staining was performed to detect colonic injury. Western blot analysis was performed to detect expression level in tight junction­associated proteins in murine colon tissue. Additionally, myeloperoxidase activity and inflammatory factor concentration were detected in colon tissue using ELISA. TUNEL and western blot assays were also performed to detect cell apoptosis, and the expression level of Sirt1/NF­κB/p53 pathway­related proteins was also determined using western blot analysis. The results revealed that Ori ameliorated clinical symptoms and pathological lesions in mice with DSS­induced UC. Furthermore, Ori protected the integrity of the colonic mucosal barrier, reduced the inflammatory response and decreased oxidative stress levels in mice with DSS­induced UC. Ori treatment also inhibited intestinal mucosal cell apoptosis. These effects may have occurred via the Sirtuin­1/NF­κB/p53 pathway. In conclusion, Ori treatment inhibited DSS­induced inflammatory response, oxidative stress and intestinal mucosal apoptosis in UC mice.


Assuntos
Colite Ulcerativa , Colite , Animais , Colite/patologia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Colo/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Diterpenos do Tipo Caurano , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Sirtuína 1/metabolismo , Proteínas de Junções Íntimas/metabolismo , Proteína Supressora de Tumor p53/metabolismo
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