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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.
BMC Plant Biol ; 22(1): 402, 2022 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-35974304

RESUMO

BACKGROUND: Plants growing in proximity to other plants are exposed to a variety of metabolites that these neighbors release into the environment. Some species produce allelochemicals to inhibit growth of neighboring plants, which in turn have evolved ways to detoxify these compounds. RESULTS: In order to understand how the allelochemical-receiving target plants respond to chemically diverse compounds, we performed whole-genome transcriptome analysis of Arabidopsis thaliana exposed to either the benzoxazinoid derivative 2-amino- 3H-phenoxazin-3-one (APO) or momilactone B. These two allelochemicals belong to two very different compound classes, benzoxazinoids and diterpenes, respectively, produced by different Poaceae crop species. CONCLUSIONS: Despite their distinct chemical nature, we observed similar molecular responses of A. thaliana to these allelochemicals. In particular, many of the same or closely related genes belonging to the three-phase detoxification pathway were upregulated in both treatments. Further, we observed an overlap between genes upregulated by allelochemicals and those involved in herbicide detoxification. Our findings highlight the overlap in the transcriptional response of a target plant to natural and synthetic phytotoxic compounds and illustrate how herbicide resistance could arise via pathways involved in plant-plant interaction.


Assuntos
Arabidopsis , Diterpenos , Arabidopsis/genética , Arabidopsis/metabolismo , Benzoxazinas/metabolismo , Benzoxazinas/farmacologia , Diterpenos/metabolismo , Diterpenos/farmacologia , Feromônios/análise , Feromônios/metabolismo , Plantas/metabolismo
3.
J Agric Food Chem ; 70(34): 10563-10570, 2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-35993186

RESUMO

Sclareol glycol is a key starting material with significant market interest for synthesizing high-value ambroxide, a sustainable substitute for ambergris in high-end fragrances. Sclareol glycol can be obtained by biotransformation of sclareol, a labdane-type diterpene, using Hyphozyma roseonigra. However, the pathway and mechanism of sclareol glycol biosynthesis remain unclear. In this study, the dynamic time course of sclareol biotransformation was explored by resting cell assays and several intermediates produced during biotransformation were detected. The results show that (1) sclareol glycol and sclareolide are not interconverted and are potentially synthesized via different metabolic pathways and (2) several putative intermediates resulting from biotransformation are featured with a labdane carbon backbone, including isomerized and oxidized analogues. A plausible transformation pathway of sclareol in H. roseonigra was proposed based on detected metabolites. This study sheds light on the biosynthetic mechanism of sclareol glycol and paves a way for the future biotechnological production of this promising compound.


Assuntos
Ascomicetos , Diterpenos , Ascomicetos/metabolismo , Biotransformação , Carbono/metabolismo , Diterpenos/metabolismo
4.
Metab Eng ; 73: 201-213, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35934176

RESUMO

The oxidized kaurene (Ox-Kau) compounds are the core structures of many important diterpenoids with biological activities and economical values. However, easy access to diverse Ox-Kau products is still limited by low natural abundance, and large-scale manufacture remain challenging due to lack of proper heterologous production. To achieve an abundant source alternative to natural extracts, we here report a highly effective Escherichia coli-based platform for the de novo production of multiple Ox-Kau molecules from simple carbon source. Pathway optimization in prokaryotic cells through modification of transmembrane CYP450 oxidases, cytochrome b5 co-expression and AlphaFold-based protein engineering improved a 50-fold yield of steviol (1.07 g L-1), a key intermediate in the kaurenoid biosynthesis. Combinatorial biosynthetic strategy further led to a series of oxidized derivatives (20-600 mg L-1) with rich oxygenated functional groups on C3, C7, C16 and C19 previously hard to be introduced. Our engineered strains not only laid a foundation for realizing the industrial fermentation of gram-scale ent-kaurene diterpenoids, but also provided a reliable platform for characterization and utilization of kaurene-modifying oxidases, which may generate naturally rare or unnatural ent-kaurenoids with potential bioactivity.


Assuntos
Alquil e Aril Transferases , Diterpenos do Tipo Caurano , Diterpenos , Alquil e Aril Transferases/metabolismo , Diterpenos/metabolismo , Diterpenos do Tipo Caurano/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Plantas/metabolismo
5.
Artigo em Inglês | MEDLINE | ID: mdl-35985449

RESUMO

Lymphatic filariasis caused by filarial nematode is an important disease leading to considerable morbidity throughout tropical countries. Even after specific elimination programs, the disease continue to spread in endemic countries. Thus newer therapeutic interventions are urgently needed to control the spread. In the present study, we have seen the effect of andrographolide (andro), a diterpenoid lactone from the leaves of Andrographis paniculata on filarial parasite Setaria cervi. There was time and concentration dependent decrease in motility and viability leading to death of parasite after 6 h of the exposure of andro. Andro showed potential antifilarial activity with an IC50 value of 24.80 µM assessed through MTT assay. There was concentration dependent decrease in the antioxidant enzymes activity and increase in proapoptotic markers after 5 h exposure of andro. Further, molecular docking analysis revealed that andro binds with filarial glutathione-S-transferase at glutathione (GSH) binding site and inhibiting enzyme activity competitively. Andro induced oxidative stress mediated apoptosis in parasites as evidenced by increase in the intracellular reactive oxygen species (ROS) and apoptotic markers.Therefore this study suggested that andro could be further explored as a new antifilarial drug.


Assuntos
Diterpenos , Parasitos , Setaria (Nematoide) , Animais , Bovinos , Diterpenos/metabolismo , Diterpenos/farmacologia , Glutationa/metabolismo , Simulação de Acoplamento Molecular , Setaria (Nematoide)/metabolismo
6.
Plant J ; 111(5): 1354-1367, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35781905

RESUMO

Momilactone A, an important plant labdane-related diterpenoid, functions as a phytoalexin against pathogens and an allelochemical against neighboring plants. The genes involved in the biosynthesis of momilactone A are found in clusters, i.e., momilactone A biosynthetic gene clusters (MABGCs), in the rice and barnyardgrass genomes. In addition, we know little about the origin and evolution of MABGCs. Here, we integrated results from comprehensive phylogeny and comparative genomic analyses of the core genes of MABGC-like clusters and MABGCs in 40 monocot plant genomes, providing convincing evidence for the birth and evolution of MABGCs in grass species. The MABGCs found in the PACMAD clade of the core grass lineage (including Panicoideae and Chloridoideae) originated from a MABGC-like cluster in Triticeae (BOP clade) via lateral gene transfer (LGT) and followed by recruitment of MAS1/2 and CYP76L1 genes. The MABGCs in Oryzoideae originated from PACMAD through another LGT event and lost CYP76L1 afterwards. The Oryza MABGC and another Oryza diterpenoid cluster c2BGC are two distinct clusters, with the latter originating from gene duplication and relocation within Oryzoideae. Further comparison of the expression patterns of the MABGC genes between rice and barnyardgrass in response to pathogen infection and allelopathy provides novel insights into the functional innovation of MABGCs in plants. Our results demonstrate LGT-mediated origination of MABGCs in grass and shed lights into the evolutionary innovation and optimization of plant biosynthetic pathways.


Assuntos
Diterpenos , Echinochloa , Oryza , Diterpenos/metabolismo , Echinochloa/genética , Echinochloa/metabolismo , Família Multigênica , Oryza/metabolismo , Plantas/metabolismo , Poaceae/genética , Poaceae/metabolismo
7.
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
8.
Metab Eng ; 73: 82-90, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35717002

RESUMO

Diterpenoids display a large and structurally diverse class of natural compounds mainly found as specialized plant metabolites. Due to their diverse biological functions they represent an essential source for various industrially relevant applications as biopharmaceuticals, nutraceuticals, and fragrances. However, commercial production utilizing their native hosts is inhibited by low abundances, limited cultivability, and challenging extraction, while the precise stereochemistry displays a particular challenge for chemical synthesis. Due to a high carbon flux through their native 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway towards photosynthetically active pigments, green microalgae hold great potential as efficient and sustainable heterologous chassis for sustainable biosynthesis of plant-derived diterpenoids. In this study, innovative synthetic biology and efficient metabolic engineering strategies were systematically combined to re-direct the metabolic flux through the MEP pathway for efficient heterologous diterpenoid synthesis in C. reinhardtii. Engineering of the 1-Deoxy-D-xylulose 5-phosphate synthase (DXS) as the main rate-limiting enzyme of the MEP pathway and overexpression of diterpene synthase fusion proteins increased the production of high-value diterpenoids. Applying fully photoautotrophic high cell density cultivations demonstrate potent and sustainable production of the high-value diterpenoid sclareol up to 656 mg L-1 with a maximal productivity of 78 mg L-1 day-1 in a 2.5 L scale photobioreactor, which is comparable to sclareol titers reached by highly engineered yeast. Consequently, this work represents a breakthrough in establishing a powerful phototrophic green cell factory for the competetive use in industrial biotechnology.


Assuntos
Diterpenos , Microalgas , Diterpenos/metabolismo , Engenharia Metabólica , Microalgas/metabolismo
9.
Immun Inflamm Dis ; 10(7): e667, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35759241

RESUMO

BACKGROUND: Herpes simplex virus-type 1 (HSV-1) can cause diseases, especially amongst neonates and immunocompromised hosts. Hence, developing a novel anti-HSV-1 drug with low-level toxicity is vital. Triptolide (TP), a diterpenoid triepoxide is a natural product with range of bioactivity qualities. METHODS: In this study, viral infection was assessed in different phases of the HSV-1 replication cycle on A549 cells, using various assays, such as adsorption inhibition assay, penetration inhibition assay, time-of-addition assay, and quantitative polymerase chain reaction (qPCR). RESULTS: The results indicate that TP can effectively inhibit HSV-1 infection in the lowest range of concentration. TP exhibited significant inhibitory effect on HSV-1 plaque formation, with 50% effective concentration (EC50) of 0.05 µM. Furthermore, the time-of-addition assay suggests that TP has viral inhibitory effects when it was added less than 8 h postinfection (h.p.i.). This result is further confirmed by decline in the expression viral immediate-early genes (ICP4, ICP22, and ICP27) in 6 h.p.i in the TP-treated group compared to the control group, evaluated by real-time qPCR. The Western blotting result was also consistent with the previous findings, which confirms that TP can positively affect ICP4 during HSV-1 infection. CONCLUSIONS: The TP also showed antiviral activity against HSV-1. This dose-dependent activity is an indication of a particular cellular component, rather than cytotoxicity that has mediated its function. Finally, the result suggest a new approach for an effective treatment option of the HSV-1 infections.


Assuntos
Diterpenos , Herpes Simples , Herpesvirus Humano 1 , Animais , Antivirais/farmacologia , Chlorocebus aethiops , Diterpenos/metabolismo , Diterpenos/farmacologia , Compostos de Epóxi , Herpes Simples/tratamento farmacológico , Humanos , Recém-Nascido , Fenantrenos , Células Vero
10.
Acta Biochim Pol ; 69(2): 429-436, 2022 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-35617158

RESUMO

Myocardial infarction is a major cause of mortality and disability worldwide. Ischemia/reperfusion injury is the key factor that results in the increase in infarct size in pathogenesis. To find a novel therapy for myocardial infarction, we have evaluated saprirearine, a natural diterpenoid, using H9c2 cardiomyocytes injured by hypoxia/reoxygenation and explored the possible mechanisms. The results showed that saprirearine improved cell survival by increasing cell viability and blocking the release of lactate dehydrogenase. Meanwhile, saprirearine was found to attenuate mitochondrial dysfunction by inhibiting calcium overload, collapse of the mitochondrial membrane potential, and opening of the mitochondrial permeability transition pore. And oxidative stress resulting from hypoxia/reoxygenation was ameliorated by saprirearine through the reduction of reactive oxygen species and malondialdehyde as well as activation of superoxide dismutase and catalase. Additionally, saprirearine inactivated cysteinyl aspartate-specific proteinase-3, the up-regulated B-cell lymphoma-2 and down-regulated Bcl-2-associated X protein, to inhibit hypoxia/reoxygenation-induced apoptosis. Further research revealed saprirearine-activated nuclear factor E2-related factor-2 in H9c2 cardiomyocytes, which is closely associated with its protective effects. These findings can provide evidence for the discovery of new therapies targeting myocardial infarction and the application of saprirearine in clinical practice.


Assuntos
Diterpenos , Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Apoptose , Hipóxia Celular , Sobrevivência Celular , Diterpenos/metabolismo , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Humanos , Hipóxia/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miócitos Cardíacos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
11.
Molecules ; 27(9)2022 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-35566116

RESUMO

Andrographolide, the principal secondary metabolite of Andrographis paniculata, displays a wide spectrum of medicinal activities. The content of andrographolide varies significantly in the species collected from different geographical regions. Therefore, this study aims at investigating the role of different abiotic factors and selecting suitable sites for the cultivation of A. paniculata with high andrographolide content using a multilayer perceptron artificial neural network (MLP-ANN) approach. A total of 150 accessions of A. paniculata collected from different regions of Odisha and West Bengal in eastern India showed a variation in andrographolide content in the range of 0.28-5.45% on a dry weight basis. The MLP-ANN was trained using climatic factors and soil nutrients as the input layer and the andrographolide content as the output layer. The best topological ANN architecture, consisting of 14 input neurons, 12 hidden neurons, and 1 output neuron, could predict the andrographolide content with 90% accuracy. The developed ANN model showed good predictive performance with a correlation coefficient (R2) of 0.9716 and a root-mean-square error (RMSE) of 0.18. The global sensitivity analysis revealed nitrogen followed by phosphorus and potassium as the predominant input variables influencing the andrographolide content. The andrographolide content could be increased from 3.38% to 4.90% by optimizing these sensitive factors. The result showed that the ANN approach is reliable for the prediction of suitable sites for the optimum andrographolide yield in A. paniculata.


Assuntos
Andrographis , Diterpenos , Andrographis paniculata , Diterpenos/metabolismo , Redes Neurais de Computação
12.
New Phytol ; 235(3): 1231-1245, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35460590

RESUMO

Rice diterpenoid phytoalexins (DPs) are secondary metabolites with a well known role in resistance to foliar pathogens. As DPs are also known to be produced and exuded by rice roots, we hypothesised that they might play an important role in plant-nematode interactions, and particularly in defence against phytoparasitic nematodes. We used transcriptome analysis on rice roots to analyse the effect of infection by the root-knot nematode Meloidogyne graminicola or treatment with resistance-inducing chemical stimuli on DP biosynthesis genes, and assessed the susceptibility of mutant rice lines impaired in DP biosynthesis to M. graminicola. Moreover, we grew these mutants and their wild-type in field soil and used metabarcoding to assess the effect of impairment in DP biosynthesis on rhizosphere and root nematode communities. We show that M. graminicola suppresses DP biosynthesis genes early in its invasion process and, conversely, that resistance-inducing stimuli transiently induce the biosynthesis of DPs. Moreover, we show that loss of DPs increases susceptibility to M. graminicola. Metabarcoding on wild-type and DP-deficient plants grown in field soil reveals that DPs significantly alter the composition of rhizosphere and root nematode communities. Diterpenoid phytoalexins are important players in basal and inducible defence against nematode pathogens of rice and help shape rice-associated nematode communities.


Assuntos
Diterpenos , Oryza , Tylenchoidea , Animais , Diterpenos/metabolismo , Oryza/metabolismo , Doenças das Plantas/genética , Rizosfera , Sesquiterpenos , Solo
13.
Mar Drugs ; 20(3)2022 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-35323517

RESUMO

Three complex polyoxygenated diterpenoids possessing uncommon tetradecahydro-2,13:6,9-diepoxybenzo[10]annulene scaffold, namely ximaoornatins A-C (1-3), one new eunicellin-type diterpene, litophynin K (4), and a related known compound, litophynol B (5) were isolated from the South China Sea soft coral Sinularia ornata. The structures and absolute configurations of 1-4 were established by extensive spectroscopic analysis, X-ray diffraction analysis, and/or modified Mosher's method. A plausible biosynthetic relationship of 1 and its potential precursor 4 was proposed. In a bioassay, none of the isolated compounds showed obvious anti-inflammatory activity on LPS-induced TNF-α release in RAW264.7 macrophages and PTP1B inhibitory effects.


Assuntos
Antozoários/química , Produtos Biológicos , Diterpenos , Animais , Antozoários/metabolismo , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/metabolismo , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Modelos Moleculares , Estrutura Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/química , Células RAW 264.7 , Fator de Necrose Tumoral alfa/metabolismo
14.
Curr Opin Plant Biol ; 66: 102189, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35196638

RESUMO

Tanshinones are the bioactive diterpenoid constituents of the traditional Chinese medicinal herb Danshen (Salvia miltiorrhiza), and are examples of the phenolic abietanes widely found within the Lamiaceae plant family. Due to the significant interest in these labdane-related diterpenoid natural products, their biosynthesis has been intensively investigated. In addition to providing the basis for metabolic engineering efforts, this work further yielded pioneering insights into labdane-related diterpenoid biosynthesis in the Lamiaceae more broadly. This includes stereochemical foreshadowing of aromatization, with novel protein domain loss in the relevant diterpene synthase, as well as broader phylogenetic conservation of the relevant enzymes. Beyond such summary of more widespread metabolism, formation of the furan ring that characterizes the tanshinones also has been recently elucidated. Nevertheless, the biocatalysts for the pair of demethylations remain unknown, and the intriguing potential connection of these reactions to the further aromatization observed in the tanshinones are speculated upon here.


Assuntos
Diterpenos , Lamiaceae , Salvia miltiorrhiza , Abietanos/química , Abietanos/metabolismo , Diterpenos/metabolismo , Lamiaceae/metabolismo , Filogenia , Salvia miltiorrhiza/química , Salvia miltiorrhiza/metabolismo
15.
Chem Biol Interact ; 355: 109849, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35150652

RESUMO

A phytochemical investigation of cytotoxic extract and fractions of Cnidoscolus quercifolius Pohl led to isolation of five terpenoids, including three lupane-type triterpenes (1-3) and two bis-nor-diterpenes (4-5). Compounds 4 (phyllacanthone) and 5 (favelanone) are commonly found in this species and have unique chemical structure. Although their cytotoxic activity against cancer cells has been previously reported, the anticancer potential of these molecules remains poorly explored. In this paper, the antimelanoma potential of phyllacanthone (PHY) was described for the first time. Cell viability assay showed a promising cytotoxic activity (IC50 = 40.9 µM) against chemoresistant human melanoma cells expressing the BRAF oncogenic mutation (A2058 cell line). After 72 h of treatment, PHY inhibited cell migration and induced apoptosis and cell cycle arrest (p < 0.05). Immunofluorescence assay showed that the pro-apoptotic effect of PHY is probably associated with tubulin depolymerization, resulting in cytoskeleton disruption of melanoma cells. Molecular docking investigation confirmed this hypothesis given that satisfactory interaction between PHY and tubulin was observed, particularly at the colchicine binding site. These results suggest PHY from C. quercifolius could be potential leader for the design of new antimelanoma drugs.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Diterpenos/química , Euphorbiaceae/química , Proteínas Proto-Oncogênicas B-raf/genética , Tubulina (Proteína)/metabolismo , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Sítios de Ligação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular , Colchicina/química , Colchicina/metabolismo , Diterpenos/metabolismo , Diterpenos/farmacologia , Euphorbiaceae/metabolismo , Humanos , Melanoma/metabolismo , Melanoma/patologia , Simulação de Acoplamento Molecular , Mutação , Casca de Planta/química , Casca de Planta/metabolismo , Extratos Vegetais/química , Proteínas Proto-Oncogênicas B-raf/metabolismo , Tubulina (Proteína)/química
16.
Int J Mol Sci ; 23(3)2022 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-35163177

RESUMO

Triptolide (TP), the main active ingredient of Tripterygium wilfordii Hook.f., displays potent anti-inflammatory, antioxidant, and antiproliferative activities. In the present study, the effect of TP on acute pancreatitis and the underlying mechanisms of the disease were investigated using a caerulein-induced animal model of acute pancreatitis (AP) and an in vitro cell model. In vivo, pretreatment with TP notably ameliorated pancreatic damage, shown as the improvement in serum amylase and lipase levels and pancreatic morphology. Meanwhile, TP modulated the infiltration of neutrophils and macrophages (Ly6G staining and CD68 staining) and decreased the levels of proinflammatory factors (TNF-α and IL-6) through inhibiting the transactivation of nuclear factor-κB (NF-κB) in caerulein-treated mice. Furthermore, TP reverted changes in oxidative stress markers, including pancreatic glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), in acute pancreatitis mice. Additionally, TP pretreatment inhibited intracellular reactive oxygen species (ROS) levels via upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and Nrf2-regulated redox genes expression (HO-1, SOD1, GPx1 and NQO1) in vitro. Taken together, our data suggest that TP exert protection against pancreatic inflammation and tissue damage by inhibiting NF-κB transactivation, modulating immune cell responses and activating the Nrf2-mediated antioxidative system, thereby alleviating acute pancreatitis.


Assuntos
Diterpenos/farmacologia , Pancreatite/tratamento farmacológico , Fenantrenos/farmacologia , Doença Aguda , Animais , Antioxidantes/farmacologia , Ceruletídeo/efeitos adversos , Ceruletídeo/farmacologia , China , Modelos Animais de Doenças , Diterpenos/metabolismo , Compostos de Epóxi/metabolismo , Compostos de Epóxi/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/metabolismo , Pancreatite/imunologia , Pancreatite/fisiopatologia , Fenantrenos/metabolismo , Espécies Reativas de Oxigênio
17.
Int J Mol Sci ; 23(3)2022 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-35163208

RESUMO

Myocardial infarction (MI) is a multifactorial global disease, recognized as one of the leading causes of cardiovascular morbidity and mortality. Timely and correct diagnoses and effective treatments could significantly reduce incidence of complications and improve patient prognoses. In this study, seven unconventional differentially expressed genes (DEGs) (MAN2A2, TNFRSF12A, SPP1, CSNK1D, PLAUR, PFKFB3, and CXCL16, collectively termed the MTSCPPC signature) were identified through integrating DEGs from six MI microarray datasets. The pathological and theranostic roles of the MTSCPPC signature in MI were subsequently analyzed. We evaluated interactions of the MTSCPPC signature with ovatodiolide, a bioactive compound isolated from Anisomeles indica (L.) Kuntze, using in silico molecular docking tools and compared it to specific inhibitors of the members of the MTSCPPC signature. Single-cell transcriptomic analysis of the public databases revealed high expression levels of the MTSCPPC signature in immune cells of adult human hearts during an MI event. The MTSCPPC signature was significantly associated with the cytokine-cytokine receptor interactions, chemokine signaling, immune and inflammatory responses, and metabolic dysregulation in MI. Analysis of a micro (mi)RNA regulatory network of the MTSCPPC signature suggested post-transcriptional activation and the roles of miRNAs in the pathology of MI. Our molecular docking analysis suggested a higher potential for ovatodiolide to target MAN2A2, CSNK1D, and TNFRSF12A. Collectively, the results derived from the present study further advance our understanding of the complex regulatory mechanisms of MI and provide a potential MI theranostic signature with ovatodiolide as a therapeutic candidate.


Assuntos
Diterpenos/farmacologia , Infarto do Miocárdio/genética , Medicina de Precisão/métodos , Quimiocina CXCL16/genética , Bases de Dados Genéticas , Diterpenos/química , Diterpenos/metabolismo , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Manosidases/genética , MicroRNAs/genética , Simulação de Acoplamento Molecular , Infarto do Miocárdio/tratamento farmacológico , Osteopontina/genética , Fosfofrutoquinase-2/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Receptor de TWEAK/genética , Transcriptoma/genética
18.
Plant Physiol ; 189(1): 99-111, 2022 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-35157086

RESUMO

Spiro-9,13-epoxy-labdane diterpenoids are commonly found in Leonurus species, particularly in Leonurus japonicus Houtt., which is a medicinal herb of long-standing use in Asia and in which such spiro-heterocycles are present in at least 38 diterpenoids. Here, through generation of a transcriptome and functional characterization of six diterpene synthases (diTPSs) from L. japonicus, including three class II diTPSs (LjTPS1, LjTPS3, and LjTPS4) and three class I diTPSs (LjTPS5, LjTPS6, and LjTPS7), formation of the spiro-9,13-epoxy-labdane backbone was elucidated, along with identification of the relevant diTPSs for production of other labdane-related diterpenes. Similar to what has been found with diTPSs from other plant species, while LjTPS3 specifically produces the carbon-9 (C9) hydroxylated bicycle peregrinol diphosphate (PPP), the subsequently acting LjTPS6 yields a mixture of four products, largely labda-13(16),14-dien-9-ol, but with substantial amounts of viteagnusin D and the C13-S/R epimers of 9,13-epoxy-labda-14-ene. Notably, structure-function analysis identified a critical residue in LjTPS6 (I420) in which single site mutations enable specific production of the 13S epimer. Indeed, extensive mutagenesis demonstrated that LjTPS6:I420G reacts with PPP to both specifically and efficiently produce 9,13S-epoxy-labda-14-ene, providing a specialized synthase for further investigation of derived diterpenoid biosynthesis. The results reported here provide a strong foundation for future studies of the intriguing spiro-9,13-epoxy-labdane diterpenoid metabolism found in L. japonicus.


Assuntos
Alquil e Aril Transferases , Diterpenos , Leonurus , Plantas Medicinais , Alquil e Aril Transferases/genética , Alquil e Aril Transferases/metabolismo , Diterpenos/metabolismo , Leonurus/metabolismo , Transcriptoma
19.
Metabolism ; 128: 155120, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34995578

RESUMO

Statin use accompanies with increased risk of new onset of type 2 diabetes, however, the underlying mechanisms remain not be fully understood and effective prevention strategies are still lacking. Herein, we find that both pharmacological and genetic inhibition of GGTase II mimic the disruption of simvastatin on hepatic insulin signaling and glucose metabolism in vitro. AAV8-mediated knockdown of liver RABGGTA, the specific subunit of GGTase II, triggers systemic glucose metabolism disorders in vivo. By adopting a small-scale siRNA screening, we identify RAB14 as a regulator of hepatic insulin signaling and glucose metabolism. Geranylgeranylation deficiency of RAB14 inhibits the phosphorylation of AKT (Ser473) and disrupts hepatic insulin signaling and glucose metabolism possibly via impeding mTORC2 complex assembly. Finally, geranylgeranyl pyrophosphate (GGPP) supplementation is sufficient to prevent simvastatin-caused disruption of hepatic insulin signaling and glucose metabolism in vitro. Geranylgeraniol (GGOH), a precursor of GGPP, is able to ameliorate simvastatin-induced systemic glucose metabolism disorders in vivo. In conclusion, our data indicate that statins-targeted mevalonate pathway regulates hepatic insulin signaling and glucose metabolism via geranylgeranylation of RAB14. GGPP/GGOH supplementation might be an effective strategy for the prevention of the diabetic effects of statins.


Assuntos
Glucose/metabolismo , Insulina/farmacologia , Fígado/metabolismo , Ácido Mevalônico/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas rab de Ligação ao GTP/fisiologia , Animais , Diterpenos/metabolismo , Células Hep G2 , Humanos , Resistência à Insulina , Masculino , Alvo Mecanístico do Complexo 2 de Rapamicina/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Transdução de Sinais , Sinvastatina/farmacologia , Transferases/antagonistas & inibidores
20.
Chem Biodivers ; 19(3): e202100757, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35092349

RESUMO

Candida species are responsible for causing invasive candidiasis with high mortality rate and their resistance to available antifungal drugs is a major clinical challenge. Biotransformation process of the labdane diterpene ent-labd-8(17)-en-15,18-dioic acid (1) carried out with Cunninghamella elegans afforded five new derivatives (compounds 2-6). Unusual regioselective hydroxylation of the methyl group at the C-20 position of labdane-type diterpene was achieved and all compounds were subjected to cytotoxicity and antifungal evaluations. Compound 1 and its derivatives were not cytotoxic to normal (MCF-10A) and tumor (MCF-7) cell lines. Compounds 2 and 3 exhibited fungistatic activity against all tested Candida strains at lower concentrations than fluconazole. Both compounds also showed the strongest fungicidal activity against C. albicans, which is the most prevalent fungal agent involved in candidemia.


Assuntos
Candida , Diterpenos , Antifúngicos/farmacologia , Biotransformação , Candida/metabolismo , Cunninghamella , Diterpenos/metabolismo , Diterpenos/farmacologia , Fluconazol , Testes de Sensibilidade Microbiana
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