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1.
PLoS One ; 17(8): e0272520, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35925998

RESUMO

Agricultural practice in adjusting planting density and harvest date are important factors for plant development and crop improvement, reaching maximum yields and enhancing the production of secondary metabolites. However, it is unclear as to the optimal planting densities during mass production that encourage consistent, high yield secondary metabolite content. For this, controlled environment, crop production facilities such as plant factories with artificial lighting (PFAL) offer opportunity to enhance quality and stabilize production of herbal plants. This study assessed the effect of plant density and harvest date on physiological responses, yield and andrographolide (AP1) content in Andrographis paniculata (Andrographis) using hydroponic conditions in a PFAL system. Andrographis, harvested at vegetative stage (30 days after transplanting; 30 DAT) and initial stage of flowering (60 DAT) exhibited no significant differences in growth parameters or andrographolide accumulation according to planting densities. Harvest time at flowering stage (90 DAT) showed the highest photosynthetic rates at a planting density of 15 plants m-2. Highest yield, number of leaves, and Andrographolide (AP1) content (mg per gram of DW in m2) were achieved at a more moderate planting density (30 plants m-2). Finally, five out of seventeen indices of leaf reflectance reveal high correlation (r = 0.8 to 1.0 and r = -0.8 to -1.0, P<0.01) with AP1 content. These results suggest that a planting density of 30 plants m-2 and harvest time of 90 DAT provide optimal growing condition under the hydroponic PFAL system.


Assuntos
Andrographis , Diterpenos , Andrographis/metabolismo , Andrographis paniculata , Diterpenos/metabolismo , Extratos Vegetais/metabolismo , Folhas de Planta/metabolismo
2.
Sci Rep ; 12(1): 11462, 2022 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-35794136

RESUMO

Lung cancer is the most malignant form of cancer and has the highest morbidity and mortality worldwide. Due to drug resistance, the current chemotherapy for lung cancer is not effective and has poor therapeutic effects. Tripchlorolide (T4), a natural extract from the plant Tripterygium wilfordii, has powerful immunosuppressive and antitumour effects and may become a potential therapeutic agent for lung cancer. Therefore, this study aimed to investigate the effect of T4 on reducing chemoresistance in lung cancer cells and to explore the mechanism. 1. A549 and A549/DDP cells were separately transfected with AEG-1 overexpression and AEG-1 knockdown plasmids. A549/DDP cells were divided into the A549/DDP empty group, T4 group, and T4 + AEG-1 overexpression group. A CCK-8 assay was used to evaluate the proliferation of cells in each group. RT-qPCR and Western blotting were used to detect the expression of AEG-1 and MDR-1. Expression of AEG-1 in A549 and A549/DDP cells was positively correlated with cisplatin resistance. When the AEG-1 protein was overexpressed in A549 cells, the lethal effect of cisplatin on A549 cells was attenuated (all P < 0.05). After the AEG-1 protein was knocked down in A549/DDP cells, cisplatin was applied. The lethal effect was significantly increased compared to that in the corresponding control cells (all P < 0.05). AEG-1 protein expression gradually decreased with increasing T4 concentration in A549 and A549/DDP cells. Resistance to cisplatin was reduced after the addition of T4 to A549/DDP cells (P < 0.05), and this effect was enhanced after transfection with the AEG-1 knockdown plasmid. T4 plays an important role in increasing the sensitivity of lung cancer cells to cisplatin.


Assuntos
Antineoplásicos , Neoplasias Pulmonares , Proteínas de Membrana , Proteínas de Ligação a RNA , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cisplatino/farmacologia , Diterpenos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Fenantrenos , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/biossíntese , Proteínas de Ligação a RNA/genética , Fatores de Transcrição/genética
3.
Int J Mol Sci ; 23(13)2022 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-35806236

RESUMO

Lesion mimic mutants (LMMs) are ideal materials for studying cell death and resistance mechanisms. Here, we identified and mapped a novel rice LMM, g380. The g380 exhibits a spontaneous hypersensitive response-like cell death phenotype accompanied by excessive accumulation of reactive oxygen species (ROS) and upregulated expression of pathogenesis-related genes, as well as enhanced resistance to Xanthomonas oryzae pv. oryzae (Xoo). Using a map-based cloning strategy, a 184,916 bp deletion on chromosome 2 that overlaps with the diterpenoid biosynthetic gene cluster was identified in g380. Accordingly, the content of diterpenoids decreased in g380. In addition, lignin, one of the physical lines of plant defense, was increased in g380. RNA-seq analysis showed 590 significantly differentially expressed genes (DEG) between the wild-type 9311 and g380, 585 of which were upregulated in g380. Upregulated genes in g380 were mainly enriched in the monolignol biosynthesis branches of the phenylpropanoid biosynthesis pathway, the plant-pathogen interaction pathway and the phytoalexin-specialized diterpenoid biosynthesis pathway. Taken together, our results indicate that the diterpenoid biosynthetic gene cluster on chromosome 2 is involved in immune reprogramming, which in turn regulates cell death in rice.


Assuntos
Diterpenos , Oryza , Xanthomonas , Morte Celular/genética , Resistência à Doença/genética , Diterpenos/metabolismo , Regulação da Expressão Gênica de Plantas , Oryza/metabolismo , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Proteínas de Plantas/metabolismo , Xanthomonas/genética
4.
Molecules ; 27(13)2022 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-35807261

RESUMO

Two new seco-labdane diterpenoids, nudiflopene N (1) and nudiflopene O (2), and four known compounds were isolated from the leaves of Callicarpa nudiflora. The structures of the new compounds were established by 1D-, 2D-NMR, and HR-ESI-MS spectral analyses. Compounds 1-3 showed inhibitory activities on lipopolysaccharide-induced nitric oxide (NO) production in RAW264.7 cells, and new compounds 1-2 exhibited more potent inhibitory activity than compound 3. The cytotoxicity of compounds 1-3 against human hepatocellular carcinoma HepG2 cells and human gastric carcinoma SGC-7901 cells were evaluated, while all of them exhibited no cytotoxicity.


Assuntos
Callicarpa , Diterpenos , Callicarpa/química , Diterpenos/química , Humanos , Lipopolissacarídeos/farmacologia , Estrutura Molecular , Folhas de Planta/química
5.
Molecules ; 27(13)2022 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-35807527

RESUMO

Ent-abietane diterpenoids are the main active constituents of Euphorbia fischeriana. In the continuing search for new anti-breast cancer drugs, 11 ent-abietane diterpenoids (1-11) were isolated from E. fischeriana. The structures of these compounds were clearly elucidated on the basis of 1D and 2D NMR spectra as well as HRESIMS data. Among them, compound 1 was a novel compound, compound 10 was isolated from Euphorbia genus for the first time, compound 11 was firstly discovered from E. fischeriana. These compounds exhibited varying degrees of growth inhibition against the MCF-10A, MCF-7, ZR-75-1 and MDA-MB-231 cell lines in vitro. The experimental data obtained permit us to identify the roles of the epoxy group, hydroxyl group and acetoxyl group on their cytotoxic activities. Extraction is an important means for the isolation, identification, and application of valuable compounds from natural plants. To maximize yields of ent-abietane diterpenoids of E. fischeriana, 17-hydroxyjolkinolide B, jolkinolide B, 17-hydroxyjolkinolide A and jolkinolide A were selected as quality controls to optimize the salting-out-assisted liquid-liquid extraction (SALLE) by response surface methodology (RSM). The optimized conditions for SALLE were 0.47 g sodium dihydrogen phosphate, 5.5 mL acetonitrile and 4.5 mL water at pH 7.5. The experimental values of 17-hydroxyjolkinolide B, jolkinolide B, 17-hydroxyjolkinolide A and jolkinolide A (2.134, 0.529, 0.396, and 0.148 mg/g, respectively) were in agreement with the predicted values, thus demonstrating the appropriateness of the model.


Assuntos
Antineoplásicos Fitogênicos , Diterpenos , Euphorbia , Neoplasias , Abietanos/análise , Abietanos/farmacologia , Antineoplásicos Fitogênicos/química , Diterpenos/química , Euphorbia/química , Estrutura Molecular , Neoplasias/tratamento farmacológico , Raízes de Plantas/química
6.
BMC Plant Biol ; 22(1): 342, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35836128

RESUMO

BACKGROUND: Rhododendron molle (Ericaceae) is a traditional Chinese medicine, which has been used to treat rheumatism and relieve pain since ancient times. The characteristic grayanoids of this plant have been demonstrated to be the chemical basis for the analgesic activity. Moreover, unlike morphine, these diterpenoids are non-addictive. Grayanoids mainly distribute in the leaves, flowers, roots, and fruits of R. molle, with low content. Currently the research on the biosynthesis of grayanoids is hindered, partially due to lack of the genomic information. RESULTS: In the present study, a total of 744 Mb sequences were generated and assembled into 13 chromosomes. An ancient whole-genome duplication event (Ad-ß) was discovered that occurred around 70 million years ago. Tandem and segmental gene duplications led to specific gene expansions in the terpene synthase and cytochrome P450 (CYP450) gene families. Two diterpene synthases were demonstrated to be responsible for the biosynthesis of 16α-hydroxy-ent-kaurane, the key precursor for grayanoids. Phylogenetic analysis revealed a species-specific bloom of the CYP71AU subfamily, which may involve the candidate CYP450s responsible for the biosynthesis of grayanoids. Additionally, three putative terpene biosynthetic gene clusters were found. CONCLUSIONS: We reported the first genome assembly of R. molle and investigated the molecular basis underpinning terpenoids biosynthesis. Our work provides a foundation for elucidating the complete biosynthetic pathway of grayanoids and studying the terpenoids diversity in R. molle.


Assuntos
Diterpenos , Ericaceae , Rhododendron , Cromossomos , Ericaceae/genética , Filogenia , Rhododendron/genética
7.
Molecules ; 27(14)2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-35889536

RESUMO

Reactivation of Epstein-Barr virus (EBV) is associated with EBV-associated malignancies and is considered to be a benefit target for treatment. Andrographolide is claimed to have antiviral and anti-tumor activities. Therefore, this study aimed to investigate the effect of andrographolide on the inhibition of EBV lytic reactivation in EBV-positive cancer cells. The cytotoxicity of andrographolide was firstly evaluated in EBV-positive cancer cells; P3HR1, AGS-EBV and HONE1-EBV cells, using an MTT assay. Herein, the spontaneous expression of EBV lytic genes; BALF5, BRLF1 and BZLF1, was significantly inhibited in andrographolide-treated cells. Accordingly, andrographolide inhibited the expression of Zta and viral production in sodium butyrate (NaB)-induced EBV lytic reactivation. Additionally, proteomics and bioinformatics analysis revealed the differentially expressed proteins that inhibit EBV lytic reactivation in all treated cell lines were functionally related with the histone modifications and chromatin organization, such as histone H3-K9 modification and histone H3-K27 methylation. Taken together, andrographolide inhibits EBV reactivation in EBV-positive cancer cells by inhibiting EBV lytic genes, probably, through the histone modifications.


Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias , Linhagem Celular , Diterpenos , Epigênese Genética , Herpesvirus Humano 4/fisiologia , Histonas/metabolismo , Humanos , Neoplasias/genética , Transativadores/genética , Ativação Viral
8.
J Org Chem ; 87(15): 9806-9814, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35852871

RESUMO

Sinuscalide A (1), featuring an uncommon 8/8-fused carbon scaffold, three new norditerpenes, sinuscalides B-D (2-4), and sinuscatone A (5), with a 5/4/9 tricyclic carbon ring system, along with four known compounds were isolated from the South China Sea soft coral Sinularia scabra. The structures of the new compounds were established by extensive spectroscopic analysis, X-ray diffraction, and electronic circular dichroism (ECD). A plausible biosynthetic pathway for 1 was proposed. In a bioassay, compound 1 showed antiviral activity against human enterovirus EV71 (IC50 = 5.0 µM) and an inhibitory effect against RANKL-induced osteoclastogenesis (92.3% inhibition at 10 µM). Compound 5 exhibited mild inhibition against Streptococcus pneumoniae and Salmonella paratyph (MIC 16 µg/mL).


Assuntos
Antozoários , Diterpenos , Animais , Antozoários/química , Antivirais/farmacologia , Carbono , Dicroísmo Circular , Diterpenos/química , Humanos , Estrutura Molecular
9.
Molecules ; 27(15)2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35897965

RESUMO

Extensive research over the past decades has identified numerous phytochemicals that could represent an important source of anti-cancer compounds. There is an immediate need for less toxic and more effective preventive and therapeutic strategies for the treatment of cancer. Natural compounds are considered suitable candidates for the development of new anti-cancer drugs due to their pleiotropic actions on target events with multiple manners. This comprehensive review highlighted the most relevant findings achieved in the screening of phytochemicals for anticancer drug development, particularly focused on a promising class of phytochemicals such as diterpenes with abietane, clerodane, and labdane skeleton. The chemical structure of these compounds, their main natural sources, and mechanisms of action were critically discussed.


Assuntos
Antineoplásicos , Diterpenos Clerodânicos , Diterpenos , Neoplasias , Abietanos/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Diterpenos/química , Diterpenos Clerodânicos/química , Diterpenos Clerodânicos/farmacologia , Humanos , Neoplasias/tratamento farmacológico , Compostos Fitoquímicos/uso terapêutico
10.
Stem Cell Res Ther ; 13(1): 326, 2022 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-35850702

RESUMO

BACKGROUND: Bone marrow mesenchymal stem cell (BMSCs) therapy is an important cell transplantation strategy in the regenerative medicine field. However, a severely ischemic microenvironment, such as nutrient depletion and hypoxia, causes a lower survival rate of transplanted BMSCs, limiting the application of BMSCs. Therefore, improving BMSCs viability in adverse microenvironments is an important means to improve the effectiveness of BMSCs therapy. OBJECTIVE: To illustrate the protective effect of andrographolide (AG) against glucose and serum deprivation under hypoxia (1% O2) (GSDH)-induced cell injury in BMSCs and investigate the possible underlying mechanisms. METHODS: An in vitro primary rat BMSCs cell injury model was established by GSDH, and cellular viability, proliferation and apoptosis were observed after AG treatment under GSDH. Reactive oxygen species levels and oxidative stress-related genes and proteins were measured by flow cytometry, RT-qPCR and Western blotting. Mitochondrial morphology, function and number were further assessed by laser confocal microscopy and flow cytometry. RESULTS: AG protected BMSCs against GSDH-induced cell injury, as indicated by increases in cell viability and proliferation and mitochondrial number and decreases in apoptosis and oxidative stress. The metabolic status of BMSCs was changed from glycolysis to oxidative phosphorylation to increase the ATP supply. We further observed that the NRF2 pathway was activated by AG, and treatment of BMSCs with a specific NRF2 inhibitor (ML385) blocked the protective effect of AG. CONCLUSION: Our results suggest that AG is a promising agent to improve the therapeutic effect of BMSCs.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Animais , Apoptose , Células da Medula Óssea/metabolismo , Diterpenos , Glucose/metabolismo , Hipóxia/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
11.
Molecules ; 27(14)2022 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-35889221

RESUMO

This study reports the isolation of three new C20 diterpenoid alkaloids, Chitralinine A-C (1-3) from the aerial parts of Delphinium chitralense. Their structures were established on the basis of latest spectral techniques and single crystal X-rays crystallographic studies of chitralinine A described basic skeleton of these compounds. All the isolated Compounds (1-3) showed strong, competitive type inhibition against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in comparison to standard allanzanthane and galanthamine however, chitralinine-C remained the most potent with IC50 value of 11.64 ± 0.08 µM against AChE, and 24.31 ± 0.33 µM against BChE, respectively. The molecular docking reflected a binding free energy of -16.400 K Cal-mol-1 for chitralinine-C, having strong interactions with active site residues, TYR334, ASP72, SER122, and SER200. The overall findings suggest that these new diterpenoid alkaloids could serve as lead drugs against dementia-related diseases including Alzheimer's disease.


Assuntos
Alcaloides , Delphinium , Diterpenos , Acetilcolinesterase/metabolismo , Alcaloides/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Delphinium/química , Diterpenos/química , Simulação de Acoplamento Molecular
12.
Molecules ; 27(14)2022 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-35889271

RESUMO

Eurycomanone (EN) is one of the representative quassinoid diterpenoids from roots of Eurycoma longifolia Jack, a natural medicine that is widely distributed in Southeast Asia. Previous studies showed that EN induces cancer cell apoptosis and exhibits anti-cancer activity, but the molecular mechanism of EN against cancer has still not been elucidated. In this study, we examined the regulatory effect of EN on autophagy to reveal the mechanism of EN-mediated colon cancer growth inhibition. First, we found that EN is able to inhibit colon cancer cell proliferation and colony formation. The angiogenesis level in cancer cells was inhibited as well. Next, the treatment of EN led to the suppression of autophagy, which was characterized by the downregulation of the LC3-II level and the formation of GFP-LC3 puncta under EN treatment in colon cancer. Moreover, we revealed that the mTOR signaling pathway was activated by EN in a time- and concentration-dependent manner. Finally, autophagy induction protected colon cancer cells from EN treatment, suggesting that autophagy improves cell survival. Taken together, our findings revealed the mechanism of EN against colon cancer through inhibiting autophagy and angiogenesis in colon cancer, supporting that the autophagy inhibitor EN could be developed to be a novel anti-cancer agent.


Assuntos
Neoplasias do Colo , Diterpenos , Eurycoma , Quassinas , Autofagia , Neoplasias do Colo/tratamento farmacológico , Diterpenos/farmacologia , Humanos , Neovascularização Patológica , Extratos Vegetais/farmacologia , Quassinas/farmacologia
13.
Molecules ; 27(14)2022 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-35889428

RESUMO

Cytokine storm is a condition in which the immune system produces an excessive number of inflammatory signals, which can result in organ failure and death. It is also known as cytokine release syndrome, CRS, or simply cytokine storm, and it has received a lot of attention recently because of the COVID-19 pandemic. It appears to be one of the reasons why some people experience life-threatening symptoms from COVID-19, a medical condition induced by SARS-CoV-2 infection. In situations where natural substances can be exploited as therapeutics to reduce cytokine storm, the drug development process has come to the rescue. In the present study, we tested the potentiality of Andrographolide, labdane diterpenoid targeting several key cytokines that are secreted as a result of cytokine storm. We used molecular docking analyses, molecular dynamics simulations, and pharmacokinetic properties to test the stability of the complexes. The compound's binding energy with some cytokines was over -6.5 Kcal/mol. Furthermore, a post-molecular dynamics (MD) study revealed that Andrographolide was extremely stable with these cytokines. The compound's pharmacokinetic measurements demonstrated excellent properties in terms of adsorption, distribution, metabolism, and excretion. Our research revealed that this compound may be effective in lowering cytokine storm and treating severe symptoms.


Assuntos
COVID-19 , Diterpenos , COVID-19/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Citocinas , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Humanos , Simulação de Acoplamento Molecular , Pandemias , SARS-CoV-2
14.
Environ Pollut ; 308: 119711, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35809713

RESUMO

Volatile organic compounds (VOCs) promote cyanobacteria dominating eutrophicated waters, with aquatic plant decrease and even disappearance. To uncover the toxic mechanism of cyanobacterial VOCs on aquatic plants, we investigated the growth, photosynthetic pigment levels, photosynthetic abilities and related gene expression in duckweed treated with ß-cyclocitral and ß-ionone, 2 main components in the VOCs. The levels of chlorophylls and carotenoids gradually declined with raising the concentration of the 2 compounds and prolonging the treatment time. Their decline should result from the down-regulation of 8 genes associated with photosynthetic pigment biosynthesis and up-regulation of 2 genes involved in carotenoid degradation. The reduction was also found in the photosystem II (PSII) efficiency and O2 evolution rate, which should result from the lowered photosynthetic pigment levels and down-regulation of 38 genes related with photosynthetic process. The frond numbers, total frond area and fresh weight gradually decreased with raising the 2 compound concentration, which may result from the lowered photosynthetic abilities as well as down-regulated expression of 7 genes associated with growth-promoting hormone biosynthesis and signal transduction. It can be speculated that cyanobacterial VOCs may poison aquatic plants by lowering the photosynthesis and growth through altering related gene expression.


Assuntos
Araceae , Cianobactérias , Compostos Orgânicos Voláteis , Aldeídos , Araceae/genética , Cianobactérias/genética , Cianobactérias/metabolismo , Diterpenos , Expressão Gênica , Norisoprenoides , Fotossíntese , Compostos Orgânicos Voláteis/metabolismo , Compostos Orgânicos Voláteis/toxicidade
15.
J Enzyme Inhib Med Chem ; 37(1): 2078-2091, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35875944

RESUMO

A series of pleuromutilin derivatives containing alkylamine and nitrogen heterocycle groups were designed and synthesised under mild conditions. The in vitro antibacterial activity of these semisynthetic derivatives against four strains of Staphylococcus aureus (MRSA ATCC 43300, S.aureus ATCC 29213, S.aureus AD3, and S.aureus 144) were evaluated by the broth dilution method. Compound 13 was found to have excellent antibacterial activity against MRSA (MIC = 0.0625 µg/mL). Furthermore, compound 13 was further studied by the time-killing kinetics and the post-antibiotic effect approach. In the mouse thigh infection model, compound 13 exhibited superior antibacterial efficacy than that of tiamulin. Meanwhile, compound 13 showed a lower inhibitory effect than that of tiamulin on RAW264.7 and 16HBE cells at the concentration of 10 µg/mL. Molecular docking study revealed that compound 13 can effectively bind to the active site of the 50S ribosome (the binding free energy = -9.66 kcal/mol).


Assuntos
Diterpenos , Staphylococcus aureus Resistente à Meticilina , Compostos Policíclicos , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Diterpenos/química , Diterpenos/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Nitrogênio/farmacologia , Compostos Policíclicos/farmacologia , Staphylococcus aureus
16.
BMC Cancer ; 22(1): 724, 2022 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-35778693

RESUMO

BACKGROUND: Extranodal natural killer/T cell lymphoma (NKTCL) is a highly aggressive type of non-Hodgkin lymphoma that facing the treatment challenges. Natural compounds are important sources for drug development because of their diverse biological and chemical properties, among which terpenoids have strong anticancer activities. METHODS: The human NK/T cell lymphoma cell line YT and peripheral blood lymphocytes isolated from NKTCL patients were treated with different concentrations of kayadiol. Then, the following experiments were performed: CCK-8 assay for cell viability, reactive oxygen species (ROS) and glutathione (GSH) assay and co-treatment with NAC, reduced GSH, or ferrostatin-1 for ferroptosis, the proteome profiling for elucidating signaling pathways, and western blot for the expression of p53, SCL7A11, and GPX4. siRNA and CRISPR/Cas9 plasmid for p53 knockout was designed and transfected into YT cells to evaluate the causal role of p53 in kayadiol-induced ferroptosis. The synergistic effect was evaluated by CCK8 assay after co-treatment of kayadiol with L-asparaginase or cisplatin. RESULTS: In this study, we found that kayadiol, a diterpenoid extracted from Torreya nucifera, exerted significant killing effect on NKTCL cells without killing the healthy lymphocytes. Subsequently, we observed that kayadiol treatment triggered significant ferroptosis events, including ROS accumulation and GSH depletion. ROS scavenger NAC, GSH, and ferroptosis inhibitor ferrostatin-1 (Fer-1) reversed kayadiol-induced cell death in NKTCL cells. Furthermore, kayadiol decreased the expression of SLC7A11 and GPX4, the negative regulatory proteins for ferroptosis. We then demonstrated that p53 was the key mediator of kayadiol-induced ferroptosis by SLC7A11/GPX4 axis through p53 knockout experiments. In addition, kayadiol exerted a synergistic effect with L-asparaginase and cisplatin in NKTCL cells. CONCLUSION: Taken together, our results suggested that the natural product kayadiol exerted anticancer effects through p53-mediated ferroptosis in NK/T cell lymphoma cells. Hence, it can serve as an effective alternative in the treatment of NK/T cell lymphoma, especially for patients exhibiting chemoresistance.


Assuntos
Diterpenos , Ferroptose , Linfoma de Células T , Asparaginase , Cisplatino , Diterpenos/farmacologia , Ferroptose/efeitos dos fármacos , Humanos , Células Matadoras Naturais/metabolismo , Linfócitos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/metabolismo
17.
Viruses ; 14(7)2022 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-35891551

RESUMO

Many drugs have been evaluated to reactivate HIV-1 from cellular reservoirs, but the off-target effects of these latency reversal agents (LRA) remain poorly defined. Transposable elements (TEs) are reactivated during HIV-1 infection, but studies of potential off-target drug effects on TE expression have been limited. We analyzed the differential expression of TEs induced by canonical and non-canonical NF-κB signaling. We evaluated the effect of PKC agonists (Bryostatin and Ingenol B) on the expression of TEs in memory CD4+ T cells. Ingenol B induced 38 differentially expressed TEs (17 HERV (45%) and 21 L1 (55%)). Interestingly, TE expression in effector memory CD4+ T cells was more affected by Bryostatin compared to other memory T-cell subsets, with 121 (107 upregulated and 14 downregulated) differentially expressed (DE) TEs. Of these, 31% (n = 37) were HERVs, and 69% (n = 84) were LINE-1 (L1). AZD5582 induced 753 DE TEs (406 HERV (54%) and 347 L1 (46%)). Together, our findings show that canonical and non-canonical NF-κB signaling activation leads to retroelement expressions as an off-target effect. Furthermore, our data highlights the importance of exploring the interaction between LRAs and the expression of retroelements in the context of HIV-1 eradication strategies.


Assuntos
Elementos de DNA Transponíveis , Infecções por HIV , Soropositividade para HIV , NF-kappa B , Latência Viral , Briostatinas/farmacologia , Linfócitos T CD4-Positivos/metabolismo , Diterpenos/farmacologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , HIV-1 , Humanos , NF-kappa B/metabolismo , Ativação Viral
18.
Viruses ; 14(7)2022 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-35891417

RESUMO

Despite the success of combination antiretroviral therapy (cART), HIV persists in low- and middle-income countries (LMIC) due to emerging drug resistance and insufficient drug accessibility. Furthermore, cART does not target latently-infected CD4+ T cells, which represent a major barrier to HIV eradication. The "shock and kill" therapeutic approach aims to reactivate provirus expression in latently-infected cells in the presence of cART and target virus-expressing cells for elimination. An attractive therapeutic prototype in LMICs would therefore be capable of simultaneously inhibiting viral replication and inducing latency reversal. Here we report that Gnidia sericocephala, which is used by traditional health practitioners in South Africa for HIV/AIDS management to supplement cART, contains at least four daphnane-type compounds (yuanhuacine A (1), yuanhuacine as part of a mixture (2), yuanhuajine (3), and gniditrin (4)) that inhibit viral replication and/or reverse HIV latency. For example, 1 and 2 inhibit HIV replication in peripheral blood mononuclear cells (PBMC) by >80% at 0.08 µg/mL, while 1 further inhibits a subtype C virus in PBMC with a half-maximal effective concentration (EC50) of 0.03 µM without cytotoxicity. Both 1 and 2 also reverse HIV latency in vitro consistent with protein kinase C activation but at 16.7-fold lower concentrations than the control prostratin. Both 1 and 2 also reverse latency in primary CD4+ T cells from cART-suppressed donors with HIV similar to prostratin but at 6.7-fold lower concentrations. These results highlight G. sericocephala and components 1 and 2 as anti-HIV agents for improving cART efficacy and supporting HIV cure efforts in resource-limited regions.


Assuntos
Diterpenos , Infecções por HIV , HIV-1 , Plantas Medicinais , Thymelaeaceae , Linfócitos T CD4-Positivos , Cromatografia Líquida de Alta Pressão , Diterpenos/farmacologia , Diterpenos/uso terapêutico , HIV-1/fisiologia , Humanos , Leucócitos Mononucleares/metabolismo , Ativação Viral , Latência Viral
19.
Org Lett ; 24(28): 5161-5165, 2022 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-35816023

RESUMO

Herein, we report the first enantioselective total synthesis of the highly complex hamigeran diterpenoid (-)-hamigeran F and its rearrangement product. The synthetic strategy features key steps of asymmetric hydrogenation, Horner-Wadsworth-Emmons olefination, and intramolecular Friedel-Crafts acylation to construct the [6,6,5]-tricyclic skeleton bearing three consecutive stereocenters, a sequence of steps involving Rosenmund reduction, Wittig reaction, dihydroxylation to assemble the α-acetoxy ketone group, and an intramolecular aldol reaction to build the tetracyclic core structure.


Assuntos
Diterpenos , Cetonas , Acilação , Hidrogenação , Estrutura Molecular , Estereoisomerismo
20.
J Nat Prod ; 85(7): 1691-1696, 2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35790346

RESUMO

The labdane diterpene hedychenone, isolated from Hedychium spicatum, is an example of a furan-containing natural product. Herein, a new and efficient method for the synthesis of 19 new thio analogues of hedychenone is reported. The present methodology exhibits a broad substrate scope with good to excellent yields without metal or base under mild reaction conditions. The natural compound 1 and four semisynthetic derivatives (3a, 3b, 3i, and 3j) exhibited strong α-glucosidase inhibition activity with IC50 values of 15.93 ± 0.29, 9.70 ± 0.33, 11.82 ± 0.06, 12.23 ± 0.33, and 12.15 ± 0.14 µg/mL, respectively. In addition, compound 3e (6.0 ± 0.04 mm; zone of inhibition) displayed antibacterial activity against Staphylococcus aureus. This study increases the chemical diversity of bioactive hedychenone derivatives and provides a direction for the development of antidiabetic agents.


Assuntos
Diterpenos , Zingiberaceae , Diterpenos/química , Hipoglicemiantes/farmacologia , Estrutura Molecular , Enxofre , Zingiberaceae/química
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