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1.
Molecules ; 26(24)2021 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-34946540

RESUMO

This study demonstrates the inhibitory effect of 42 pyrimidonic pharmaceuticals (PPs) on the 3-chymotrypsin-like protease of SARS-CoV-2 (3CLpro) through molecular docking, molecular dynamics simulations, and free binding energies by means of molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) and molecular mechanics-generalized Born surface area (MM-GBSA). Of these tested PPs, 11 drugs approved by the US Food and Drug Administration showed an excellent binding affinity to the catalytic residues of 3CLpro of His41 and Cys145: uracil mustard, cytarabine, floxuridine, trifluridine, stavudine, lamivudine, zalcitabine, telbivudine, tipiracil, citicoline, and uridine triacetate. Their percentage of residues involved in binding at the active sites ranged from 56 to 100, and their binding affinities were in the range from -4.6 ± 0.14 to -7.0 ± 0.19 kcal/mol. The molecular dynamics as determined by a 200 ns simulation run of solvated docked complexes confirmed the stability of PP conformations that bound to the catalytic dyad and the active sites of 3CLpro. The free energy of binding also demonstrates the stability of the PP-3CLpro complexes. Citicoline and uridine triacetate showed free binding energies of -25.53 and -7.07 kcal/mol, respectively. Therefore, I recommend that they be repurposed for the fight against COVID-19, following proper experimental and clinical validation.


Assuntos
COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases Semelhantes à Papaína de Coronavírus/antagonistas & inibidores , Reposicionamento de Medicamentos/métodos , Inibidores de Proteases/farmacologia , SARS-CoV-2/efeitos dos fármacos , Acetatos/química , Acetatos/farmacologia , Antivirais/química , Antivirais/farmacologia , Citidina Difosfato Colina/química , Citidina Difosfato Colina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/química , Uridina/análogos & derivados , Uridina/química , Uridina/farmacologia
2.
Molecules ; 26(20)2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34684788

RESUMO

It is known that Senna obtusifolia has been used in medicine since ancient times due to the content of many valuable compounds with a pro-health effect. One of them is betulinic acid, which is a pentacyclic triterpene with antimalarial, antiviral, anti-inflammatory and anticancer properties. In this work, a continuation of our previous research, an attempt was made to increase the level of betulinic acid accumulation by the cultivation of transgenic hairy roots that overexpress the squalene synthase gene in a 10 L sprinkle bioreactor with methyl jasmonate elicitation. We present that the applied strategy allowed us to increase the content of betulinic acid in hairy root cultures to the level of 48 mg/g dry weight. The obtained plant extracts showed a stronger cytotoxic effect on the U87MG glioblastoma cell line than the roots grown without elicitors. Additionally, the induction of apoptosis, reduction of mitochondrial membrane potential, chromosomal DNA fragmentation and activation of caspase cascades are demonstrated. Moreover, the tested extract showed inhibition of topoisomerase I activity.


Assuntos
Acetatos/farmacologia , Antineoplásicos Fitogênicos/metabolismo , Ciclopentanos/farmacologia , Oxilipinas/farmacologia , Triterpenos Pentacíclicos/metabolismo , Senna (Planta)/efeitos dos fármacos , Senna (Planta)/metabolismo , Células A549 , Antineoplásicos Fitogênicos/biossíntese , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Reatores Biológicos , Biotecnologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Fragmentação do DNA/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Triterpenos Pentacíclicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Reguladores de Crescimento de Plantas/farmacologia , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Plantas Geneticamente Modificadas , Plantas Medicinais/efeitos dos fármacos , Plantas Medicinais/crescimento & desenvolvimento , Plantas Medicinais/metabolismo , Senna (Planta)/crescimento & desenvolvimento
3.
Planta ; 254(5): 89, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34586513

RESUMO

MAIN CONCLUSION: Transcriptome and biochemical analyses suggested that, while suppression of multiple flavonoids and anthocyanins occurs at least partially at the transcriptional level, increased biosynthesis of non-jasmonate phyto-oxylipins is likely controlled non-transcriptionally. Methyl jasmonate (MeJA) produced in plants can mediate their response to environmental stresses. Exogenous application of MeJA has also shown to activate signaling pathways and induce phytoalexin accumulation in many plant species. To understand how pomegranate plants respond biochemically to environmental stresses, metabolite analysis was conducted in pomegranate leaves subjected to MeJA application and revealed unique changes in hydrolyzable tannins, flavonoids, and phyto-oxylipins. Additionally, transcriptome and real-time qPCR analyses of mock- and MeJA-treated pomegranate leaves identified differentially expressed metabolic genes and transcription factors that are potentially involved in the control of hydrolyzable tannin, flavonoid, and phyto-oxylipin pathways. Molecular, biochemical, and bioinformatic characterization of the only lipoxygenase with sustained, MeJA-induced expression showed that it is capable of oxidizing polyunsaturated fatty acids, though not located in the subcellular compartment where non-jasmonate (non-JA) phyto-oxylipins were produced. These results collectively suggested that while the broad suppression of flavonoids and anthocyanins is at least partially controlled at the transcriptional level, the induced biosynthesis of non-JA phyto-oxylipins is likely not regulated transcriptionally. Overall, a better understanding of how pomegranate leaves respond to environmental stresses will not only promote plant health and productivity, but also have an impact on human health as fruits produced by pomegranate plants are a rich source of nutritional compounds.


Assuntos
Oxilipinas , Romã (Fruta) , Acetatos/farmacologia , Antocianinas , Ciclopentanos/farmacologia , Flavonoides , Frutas , Regulação da Expressão Gênica de Plantas , Taninos Hidrolisáveis , Oxilipinas/farmacologia , Folhas de Planta
4.
Int J Mol Sci ; 22(18)2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34576236

RESUMO

Wounds in tissues provide a pathway of entry for pathogenic fungi and bacteria in plants. Plants respond to wounding by regulating the expression of genes involved in their defense mechanisms. To analyze this response, we investigated the defense-related genes induced by wounding in the leaves of Senna tora using RNA sequencing. The genes involved in jasmonate and ethylene biosynthesis were strongly induced by wounding, as were a large number of genes encoding transcription factors such as ERFs, WRKYs, MYBs, bHLHs, and NACs. Wounding induced the expression of genes encoding pathogenesis-related (PR) proteins, such as PR-1, chitinase, thaumatin-like protein, cysteine proteinase inhibitor, PR-10, and plant defensin. Furthermore, wounding led to the induction of genes involved in flavonoid biosynthesis and the accumulation of kaempferol and quercetin in S. tora leaves. All these genes were expressed systemically in leaves distant from the wound site. These results demonstrate that mechanical wounding can lead to a systemic defense response in the Caesalpinioideae, a subfamily of the Leguminosae. In addition, a co-expression analysis of genes induced by wounding provides important information about the interactions between genes involved in plant defense responses.


Assuntos
Acetatos/farmacologia , Ciclopentanos/farmacologia , Fabaceae/genética , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Oxilipinas/farmacologia , Reguladores de Crescimento de Plantas/farmacologia , Imunidade Vegetal , Plantas/efeitos dos fármacos , Etilenos/química , Perfilação da Expressão Gênica , Genes de Plantas , Quempferóis/farmacologia , Doenças das Plantas , Folhas de Planta/metabolismo , Proteínas de Plantas/genética , Quercetina/farmacologia , RNA-Seq
5.
J Enzyme Inhib Med Chem ; 36(1): 1996-2009, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34525898

RESUMO

Microtubule dynamics are crucial for multiple cell functions, and cancer cells are particularly sensitive to microtubule-modulating agents. Here, we describe the design and synthesis of a series of (Z)-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl)-N-phenylacetamide derivatives and evaluation of their microtubule-modulating and anticancer activities in vitro. Proliferation assays identified I20 as the most potent of the antiproliferative compounds, with 50% inhibitory concentrations ranging from 7.0 to 20.3 µM with A549, PC-3, and HepG2 human cancer cell lines. Compound I20 also disrupted cancer A549 cell migration in a concentration-dependent manner. Immunofluorescence microscopy, transmission electron microscopy, and tubulin polymerisation assays suggested that compound I20 promoted protofilament assembly. In support of this possibility, computational docking studies revealed a strong interaction between compound I20 and tubulin Arg ß369, which is also the binding site for the anticancer drug Taxol. Our results suggest that (Z)-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl)-N-phenylacetamide derivatives could have utility for the development of microtubule-stabilising therapeutic agents.


Assuntos
Acetatos/farmacologia , Amidas/farmacologia , Antineoplásicos/farmacologia , Descoberta de Drogas , Microtúbulos/efeitos dos fármacos , Rodanina/farmacologia , Moduladores de Tubulina/farmacologia , Células A549 , Acetatos/síntese química , Acetatos/química , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Microtúbulos/metabolismo , Estrutura Molecular , Polimerização/efeitos dos fármacos , Rodanina/análogos & derivados , Rodanina/química , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
6.
Pharmacology ; 106(9-10): 469-476, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34350893

RESUMO

BACKGROUND: The coronavirus disease-19 (COVID-19) pandemic is a serious devastating disease and has posed a global health emergency. So far, there is not any specific therapy approved till date to control the clinical symptoms of the disease. Remdesivir has been approved by the FDA as an emergency clinical therapy. But it may not be effective alone to control the disease as it can only control the viral replication in the host. SUMMARY: This article summarizes the possible therapeutic potential and benefits of using montelukast, a cysteinyl leukotriene 1 (CysLT1) receptor antagonist, to control COVID-19 pathophysiology. Montelukast has shown anti-inflammatory effects, reduced cytokine production, improvement in post-infection cough production and other lung complications. Key Messages: Recent reports clearly indicate a distinct role of CysLT-regulated cytokines and immunological signaling in COVID-19. Thus, montelukast may have a clinical potential to control lung pathology during COVID-19.


Assuntos
Acetatos/farmacologia , COVID-19/tratamento farmacológico , Ciclopropanos/farmacologia , Antagonistas de Leucotrienos/farmacologia , Quinolinas/farmacologia , Sulfetos/farmacologia , Acetatos/uso terapêutico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/farmacologia , Alanina/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/metabolismo , COVID-19/fisiopatologia , Ciclopropanos/uso terapêutico , Humanos , Antagonistas de Leucotrienos/uso terapêutico , Quinolinas/uso terapêutico , Receptores de Leucotrienos/metabolismo , Sulfetos/uso terapêutico
7.
BMC Plant Biol ; 21(1): 360, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34362300

RESUMO

BACKGROUND: Dendrobium catenatum belongs to the Orchidaceae, and is a precious Chinese herbal medicine. In the past 20 years, D. catenatum industry has developed from an endangered medicinal plant to multi-billion dollar grade industry. The necrotrophic pathogen Sclerotium delphinii has a devastating effection on over 500 plant species, especially resulting in widespread infection and severe yield loss in the process of large-scale cultivation of D. catenatum. It has been widely reported that Jasmonate (JA) is involved in plant immunity to pathogens, but the mechanisms of JA-induced plant resistance to S. delphinii are unclear. RESULTS: In the present study, the role of JA in enhancing D. catenatum resistance to S. delphinii was investigated. We identified 2 COI1, 13 JAZ, and 12 MYC proteins in D. catenatum genome. Subsequently, systematic analyses containing phylogenetic relationship, gene structure, protein domain, and motif architecture of core JA pathway proteins were conducted in D. catenatum and the newly characterized homologs from its closely related orchid species Phalaenopsis equestris and Apostasia shenzhenica, along with the well-investigated homologs from Arabidopsis thaliana and Oryza sativa. Public RNA-seq data were investigated to analyze the expression patterns of D. catenatum core JA pathway genes in various tissues and organs. Transcriptome analysis of MeJA and S. delphinii treatment showed exogenous MeJA changed most of the expression of the above genes, and several key members, including DcJAZ1/2/5 and DcMYC2b, are involved in enhancing defense ability to S. delphinii in D. catenatum. CONCLUSIONS: The findings indicate exogenous MeJA treatment affects the expression level of DcJAZ1/2/5 and DcMYC2b, thereby enhancing D. catenatum resistance to S. delphinii. This research would be helpful for future functional identification of core JA pathway genes involved in breeding for disease resistance in D. catenatum.


Assuntos
Basidiomycota/patogenicidade , Ciclopentanos/metabolismo , Dendrobium/microbiologia , Oxilipinas/metabolismo , Imunidade Vegetal/fisiologia , Proteínas de Plantas/genética , Acetatos/farmacologia , Ciclopentanos/farmacologia , Dendrobium/efeitos dos fármacos , Dendrobium/imunologia , Dendrobium/metabolismo , Resistência à Doença/genética , Regulação da Expressão Gênica de Plantas , Família Multigênica , Oxilipinas/farmacologia , Filogenia , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Proteínas de Plantas/imunologia , Transdução de Sinais/genética
8.
Int J Mol Sci ; 22(15)2021 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-34360691

RESUMO

Two-line hybrid rice systems represent a new technical approach to utilizing the advantages of rice hybrids. However, the mechanism underlying the male sterile-line fertility transition in rice remains unclear. Peiai 64S (PA64S) is a photoperiod- and thermo-sensitive genic male sterile (PTGMS) line in which male sterility manifests at an average temperature above 23.5 °C under long-day (LD) conditions. Nongken 58S (NK58S) is a LD-sensitive genic male sterile (PGMS) rice that is sterile under LD conditions (above 13.75 h-day). In contrast, D52S is a short-day (SD)-PGMS line that manifests male sterility under SD conditions (below 13.5 h-day). In this study, we obtained fertile and sterile plants from all three lines and performed transcriptome analyses on the anthers of the plants. Gene ontology (GO) analysis suggested that the differentially expressed genes identified were significantly enriched in common terms involved in the response to jasmonic acid (JA) and in JA biosynthesis. On the basis of the biochemical and molecular validation of dynamic, tissue-specific changes in JA, indole-3-acetic acid (IAA) levels, gibberellin (GA) levels, and JA biosynthetic enzyme activities and expression, we proposed that JA could play a pivotal role in viable pollen production through its initial upregulation, constant fluctuation and leaf-spikelet signaling under certain fertility-inducing conditions. Furthermore, we also sprayed methyl jasmonate (MEJA) and salicylhydroxamic acid (SHAM) on the plants, thereby achieving fertility reversal in the PGMS lines NK58S and D52S, with 12.91-63.53% pollen fertility changes. Through qPCR and enzyme activity analyses, we identified two key enzymes-allene oxide synthase (AOS) and allene oxide cyclase (AOC)-that were produced and upregulated by 20-500-fold in PGMS in response to spraying; the activities of these enzymes reversed pollen fertility by influencing the JA biosynthetic pathway. These results provide a new understanding of hormone interactions and networks in male-sterile rice based on the role of JA that will help us to better understand the potential regulatory mechanisms of fertility development in rice in the future.


Assuntos
Ciclopentanos/metabolismo , Oxirredutases Intramoleculares/genética , Oryza/metabolismo , Oxilipinas/metabolismo , Pólen/crescimento & desenvolvimento , Transdução de Sinais , Acetatos/farmacologia , Ciclopentanos/farmacologia , Fertilidade , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Oryza/genética , Oryza/fisiologia , Oxilipinas/farmacologia , Proteínas de Plantas/genética , Pólen/metabolismo , Salicilamidas/farmacologia
9.
J Enzyme Inhib Med Chem ; 36(1): 1916-1921, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34461785

RESUMO

An earlier described three-component variant of the Castagnoli-Cushman reaction employing homophthalic anhydrides, carbonyl compound and ammonium acetate was applied towards the preparation of 1-oxo-3,4-dihydroisoquinoline-4-carboxamides with variable substituent in position 3. These compounds displayed inhibitory activity towards poly(ADP-ribose) polymerase (PARP), a clinically validated cancer target. The most potent compound (PARP1/2 IC50 = 22/4.0 nM) displayed the highest selectivity towards PARP2 in the series (selectivity index = 5.5), more advantageous ADME prameters compared to the clinically used PARP inhibitor Olaparib.


Assuntos
Acetatos/química , Antineoplásicos/química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Poli(ADP-Ribose) Polimerases/metabolismo , Quinolonas/química , Acetatos/farmacologia , Sequência de Aminoácidos , Antineoplásicos/farmacologia , Sítios de Ligação , Dano ao DNA/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , NAD/metabolismo , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade
10.
J Chem Ecol ; 47(8-9): 810-818, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34463894

RESUMO

Adults of many mosquito species feed on plants to obtain metabolic energy and to enhance reproduction. Mosquitoes primarily rely on olfaction to locate plants and are known to respond to a range of plant volatiles. We studied the olfactory response of the yellow fever mosquito Aedes aegypti to methyl jasmonate (MeJA) and cis-jasmone (CiJA), volatile compounds originating from the octadecanoid signaling pathway that plays a key role in plant defense against herbivores. Specifically, we investigated how Ae. aegypti of different ages responded to elevated levels of CiJA in two attractive odor contexts, either derived from Lima bean plants or human skin. Aedes aegypti females landed significantly less often on a surface with CiJA and MeJA compared to the solvent control, CiJA exerting a stronger reduction in landing than MeJA. Odor context (plant or human) had no significant main effect on the olfactory responses of Ae. aegypti females to CiJA. Mosquito age significantly affected the olfactory response, older females (7-9 d) responding more strongly to elevated levels of CiJA than young females (1-3 d) in either odor context. Our results show that avoidance of CiJA by Ae. aegypti is independent of odor background, suggesting that jasmonates are inherently aversive cues to these mosquitoes. We propose that avoidance of plants with elevated levels of jasmonates is adaptive to mosquitoes to reduce the risk of encountering predators that is higher on these plants, i.e. by avoiding 'enemy-dense-space'.


Assuntos
Aedes/fisiologia , Comportamento Animal/efeitos dos fármacos , Ciclopentanos/farmacologia , Oxilipinas/farmacologia , Phaseolus/química , Pele/química , Acetatos/química , Acetatos/farmacologia , Envelhecimento , Animais , Ciclopentanos/química , Feminino , Humanos , Isomerismo , Estágios do Ciclo de Vida , Odorantes/análise , Oxilipinas/química , Phaseolus/metabolismo , Pele/metabolismo , Compostos Orgânicos Voláteis/química , Compostos Orgânicos Voláteis/farmacologia
11.
Biomed Res Int ; 2021: 9930210, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34395628

RESUMO

The present study was aimed at isolating endophytic fungi from the Asian culinary and medicinal plant Lilium davidii and analyzing its antifungal and plant growth-promoting effects. In this study, the fungal endophyte Acremonium sp. Ld-03 was isolated from the bulbs of L. davidii and identified through morphological and molecular analysis. The molecular and morphological analysis confirmed the endophytic fungal strain as Acremonium sp. Ld-03. Antifungal effects of Ld-03 were observed against Fusarium oxysporum, Botrytis cinerea, Botryosphaeria dothidea, and Fusarium fujikuroi. The highest growth inhibition, i.e., 78.39 ± 4.21%, was observed for B. dothidea followed by 56.68 ± 4.38%, 43.62 ± 3.81%, and 20.12 ± 2.45% for B. cinerea, F. fujikuroi, and F. oxysporum, respectively. Analysis of the ethyl acetate fraction through UHPLC-LTQ-IT-MS/MS revealed putative secondary metabolites which included xanthurenic acid, valyl aspartic acid, gancidin W, peptides, and cyclic dipeptides such as valylarginine, cyclo-[L-(4-hydroxy-Pro)-L-leu], cyclo(Pro-Phe), and (3S,6S)-3-benzyl-6-(4-hydroxybenzyl)piperazine-2,5-dione. Other metabolites included (S)-3-(4-hydroxyphenyl)-2-((S)-pyrrolidine-2-carboxamido)propanoic acid, dibutyl phthalate (DBP), 9-octadecenamide, D-erythro-C18-Sphingosine, N-palmitoyl sphinganine, and hydroxypalmitoyl sphinganine. The strain Ld-03 showed indole acetic acid (IAA) production with or without the application of exogenous tryptophan. The IAA ranged from 53.12 ± 3.20 µg ml-1 to 167.71 ± 7.12 µg ml-1 under different tryptophan concentrations. The strain was able to produce siderophore, and its production was significantly decreased with increasing Fe(III) citrate concentrations in the medium. The endophytic fungal strain also showed production of organic acids and phosphate solubilization activity. Plant growth-promoting effects of the strain were evaluated on in vitro seedling growth of Allium tuberosum. Application of 40% culture dilution resulted in a significant increase in root and shoot length, i.e., 24.03 ± 2.71 mm and 37.27 ± 1.86 mm, respectively, compared to nontreated control plants. The fungal endophyte Ld-03 demonstrated the potential of conferring disease resistance and plant growth promotion. Therefore, we conclude that the isolated Acremonium sp. Ld-03 should be further investigated before utilization as a biocontrol agent and plant growth stimulator.


Assuntos
Acremonium/química , Antifúngicos/farmacologia , Ascomicetos/crescimento & desenvolvimento , Botrytis/crescimento & desenvolvimento , Fusarium/crescimento & desenvolvimento , Lilium/microbiologia , Reguladores de Crescimento de Plantas/farmacologia , Acetatos/química , Acetatos/farmacologia , Acremonium/isolamento & purificação , Acremonium/fisiologia , Antifúngicos/química , Ascomicetos/efeitos dos fármacos , Botrytis/efeitos dos fármacos , Cebolinha-Francesa/efeitos dos fármacos , Cebolinha-Francesa/crescimento & desenvolvimento , Cromatografia Líquida de Alta Pressão , Resistência à Doença , Endófitos/isolamento & purificação , Endófitos/fisiologia , Fusarium/efeitos dos fármacos , Ácidos Indolacéticos/química , Ácidos Indolacéticos/isolamento & purificação , Ácidos Indolacéticos/farmacologia , Metabolômica/métodos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Desenvolvimento Vegetal , Reguladores de Crescimento de Plantas/química , Reguladores de Crescimento de Plantas/isolamento & purificação , Raízes de Plantas/microbiologia , Metabolismo Secundário , Espectrometria de Massas em Tandem
12.
Sci Rep ; 11(1): 16913, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413433

RESUMO

Sandalwood (Santalum album L.) is highly valued for its fragrant heartwood and extracted oil. Santalols, which are the main components of that oil, are terpenoids, and these are biosynthesized via the mevalonic acid (MVA) pathway. Mevalonate kinase (MK) and phosphomevalonate kinase (PMK) are key enzymes in the MVA pathway. Little is known about the genes that encode MK and PMK in S. album or the mechanism that regulates their expression. To isolate and identify the functional genes involved in santalol biosynthesis in S. album, an MK gene designated as SaMK, and a PMK gene designated as SaPMK, were cloned from S. album. The sequences of these genes were analyzed. A bioinformatics analysis was conducted to assess the homology of SaMK and SaPMK with MK and PMK genes from other plants. The subcellular localization of SaMK and SaPMK proteins was also investigated, as was the functional complementation of SaMK and SaPMK in yeast. Our results show that the full-length cDNA sequences of SaMK and SaPMK were 1409 bp and 1679 bp long, respectively. SaMK contained a 1381 bp open reading frame (ORF) encoding a polypeptide of 460 amino acids and SaPMK contained a 1527 bp ORF encoding a polypeptide of 508 amino acids. SaMK and SaPMK showed high homology with MK and PMK genes of other plant species. Functional complementation of SaMK in a MK-deficient mutant yeast strain YMR208W and SaPMK in a PMK-deficient mutant yeast strain YMR220W confirmed that cloned SaMK and SaPMK cDNA encode a functional MK and PMK, respectively, mediating MVA biosynthesis in yeast. An analysis of tissue expression patterns revealed that SaMK and SaPMK were constitutively expressed in all the tested tissues. SaMK was highly expressed in young leaves but weakly expressed in sapwood. SaPMK was highly expressed in roots and mature leaves, but weakly expressed in young leaves. Induction experiments with several elicitors showed that SaMK and SaPMK expression was upregulated by methyl jasmonate. These results will help to further study the role of MK and PMK genes during santalol biosynthesis in S. album.


Assuntos
Regulação da Expressão Gênica de Plantas , Genes de Plantas , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Fosfato)/genética , Santalum/enzimologia , Santalum/genética , Acetatos/farmacologia , Sequência de Aminoácidos , Clonagem Molecular , Biologia Computacional , Ciclopentanos/farmacologia , DNA Complementar/genética , Evolução Molecular , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Especificidade de Órgãos/efeitos dos fármacos , Especificidade de Órgãos/genética , Oxilipinas/farmacologia , Fosfotransferases (Aceptor do Grupo Álcool)/química , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Fosfotransferases (Aceptor do Grupo Fosfato)/química , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo , Filogenia , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/genética , Proteínas de Plantas/química , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/genética , Brotos de Planta/efeitos dos fármacos , Brotos de Planta/genética , Domínios Proteicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Saccharomyces cerevisiae/metabolismo , Santalum/efeitos dos fármacos , Frações Subcelulares/metabolismo
13.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445369

RESUMO

Annexin (Ann) is a polygenic, evolutionarily conserved, calcium-dependent and phospholipid-binding protein family, which plays key roles in plant growth, development, and stress response. However, a comprehensive understanding of CaAnn genes of pepper (Capsicum annuum) at the genome-wide level is limited. Based on the available pepper genomic information, we identified 15 members of the CaAnn gene family. Phylogenetic analysis showed that CaAnn proteins could be categorized into four different orthologous groups. Real time quantitative RT-PCR analysis showed that the CaAnn genes were tissue-specific and were widely expressed in pepper leaves after treatments with cold, salt, and drought, as well as exogenously applied MeJA and ABA. In addition, the function of CaAnn9 was further explored using the virus-induced gene silencing (VIGS) technique. CaAnn9-silenced pepper seedlings were more sensitive to salt stress, reflected by the degradation of chlorophyll, the accumulation of reactive oxygen species (ROS), and the decrease of antioxidant defense capacity. This study provides important information for further study of the role of pepper CaAnn genes and their coding proteins in growth, development, and environmental responses.


Assuntos
Anexinas/genética , Capsicum/crescimento & desenvolvimento , Perfilação da Expressão Gênica/métodos , Tolerância ao Sal , Ácido Abscísico/farmacologia , Acetatos/farmacologia , Capsicum/efeitos dos fármacos , Capsicum/genética , Ciclopentanos/farmacologia , Evolução Molecular , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Especificidade de Órgãos , Oxilipinas/farmacologia , Filogenia , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/genética , Folhas de Planta/crescimento & desenvolvimento , Proteínas de Plantas/genética , Sequenciamento Completo do Genoma
14.
Sci Rep ; 11(1): 14770, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285266

RESUMO

Pink stem borer (PSB) causes considerable yield losses to maize. Plant-insect interactions have significant implications for sustainable pest management. The present study demonstrated that PSB feeding, mechanical wounding, a combination of mechanical wounding and PSB regurgitation and exogenous application of methyl jasmonate have induced phenolic compound mediated defense responses both at short term (within 2 days of treatment) and long term (in 15 days of treatment) in leaf and stalk tissues of maize. The quantification of two major defense related phenolic compounds namely p-Coumaric acid (p-CA) and ferulic acid (FA) was carried out through ultra-fast liquid chromatography (UFLC) at 2 and 15 days after imposing the above treatments. The p-CA content induced in leaf tissues of maize genotypes were intrinsically higher when challenged by PSB attack at V3 and V6 stages in short- and long-term responses. Higher p-CA content was observed in stalk tissues upon wounding and regurgitation in short- and long-term responses at V3 and V6 stages. Significant accumulation of FA content was also observed in leaf tissues in response to PSB feeding at V3 stage in long-term response while at V6 stage it was observed both in short- and long-term responses. In stalk tissues, methyl jasmonate induced higher FA content in short-term response at V3 stage. However, at V6 stage PSB feeding induced FA accumulation in the short-term while, wounding and regurgitation treatment-induced defense responses in the long-term. In general, the resistant (DMRE 63, CM 500) and moderately resistant genotypes (WNZ ExoticPool) accumulated significantly higher contents of p-CA and FA content than susceptible ones (CM 202, BML 6) in most of the cases. The study indicates that phenolic mediated defense responses in maize are induced by PSB attack followed by wounding and regurgitation compared to the other induced treatments. Furthermore, the study confirmed that induced defense responses vary with plant genotype, stage of crop growth, plant tissue and short and long-term responses. The results of the study suggested that the Phenolic acids i.e. p-CA and FA may contribute to maize resistance mechanisms in the maize-PSB interaction system.


Assuntos
Acetatos/farmacologia , Ácidos Cumáricos/isolamento & purificação , Ciclopentanos/farmacologia , Mariposas/patogenicidade , Oxilipinas/farmacologia , Zea mays/crescimento & desenvolvimento , Animais , Parede Celular/química , Cromatografia Líquida , Resistência à Doença , Ácidos Graxos/química , Folhas de Planta/química , Zea mays/química , Zea mays/efeitos dos fármacos , Zea mays/parasitologia
15.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299302

RESUMO

Short-chain fatty acid (SCFA) acetate, a byproduct of dietary fiber metabolism by gut bacteria, has multiple immunomodulatory functions. The anti-inflammatory role of acetate is well documented; however, its effect on monocyte chemoattractant protein-1 (MCP-1) production is unknown. Similarly, the comparative effect of SCFA on MCP-1 expression in monocytes and macrophages remains unclear. We investigated whether acetate modulates TNFα-mediated MCP-1/CCL2 production in monocytes/macrophages and, if so, by which mechanism(s). Monocytic cells were exposed to acetate with/without TNFα for 24 h, and MCP-1 expression was measured. Monocytes treated with acetate in combination with TNFα resulted in significantly greater MCP-1 production compared to TNFα treatment alone, indicating a synergistic effect. On the contrary, treatment with acetate in combination with TNFα suppressed MCP-1 production in macrophages. The synergistic upregulation of MCP-1 was mediated through the activation of long-chain fatty acyl-CoA synthetase 1 (ACSL1). However, the inhibition of other bioactive lipid enzymes [carnitine palmitoyltransferase I (CPT I) or serine palmitoyltransferase (SPT)] did not affect this synergy. Moreover, MCP-1 expression was significantly reduced by the inhibition of p38 MAPK, ERK1/2, and NF-κB signaling. The inhibition of ACSL1 attenuated the acetate/TNFα-mediated phosphorylation of p38 MAPK, ERK1/2, and NF-κB. Increased NF-κB/AP-1 activity, resulting from acetate/TNFα co-stimulation, was decreased by ACSL1 inhibition. In conclusion, this study demonstrates the proinflammatory effects of acetate on TNF-α-mediated MCP-1 production via the ACSL1/MAPK/NF-κB axis in monocytic cells, while a paradoxical effect was observed in THP-1-derived macrophages.


Assuntos
Acetatos/farmacologia , Quimiocina CCL2/biossíntese , Ácidos Graxos Voláteis/farmacologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Acetatos/administração & dosagem , Quimiocina CCL2/genética , Coenzima A Ligases/antagonistas & inibidores , Coenzima A Ligases/metabolismo , Sinergismo Farmacológico , Inibidores Enzimáticos/farmacologia , Ácidos Graxos Voláteis/administração & dosagem , Humanos , Sistema de Sinalização das MAP Quinases , Modelos Biológicos , Monócitos/imunologia , NF-kappa B/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células THP-1 , Triazenos/farmacologia , Fator de Necrose Tumoral alfa/administração & dosagem , Fator de Necrose Tumoral alfa/farmacologia
16.
Plant Sci ; 310: 110976, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34315592

RESUMO

NAM, ATAF1/2, and CUC2 (NAC) proteins regulate plant responses to salt stress. However, the molecular mechanisms by which NAC proteins regulate salt-induced programmed cell death (PCD) are unclear. We identified 56 NAC genes, 35 of which had complete open reading frames with complete NAM domain, in the R. trigyna transcriptome. Salt stress and methyl jasmonate (MeJA) mediated PCD-induced leaf senescence in R. trigyna seedlings. Salt stress accelerated endogenous JA biosynthesis, upregulating RtNAC100 expression. This promoted salt-induced leaf senescence in R. trigyna by regulating RtRbohE and RtSAG12/20 and enhancing ROS accumulation. Transgenic assays showed that RtNAC100 overexpression aggravated salt-induced PCD in transgenic lines by promoting ROS and Na+ accumulation, ROS-Ca2+ hub activation, and PCD-related gene expression. Therefore, RtNAC100 induces PCD via the MeJA signaling pathway in R. trigyna under salt stress.


Assuntos
Acetatos/farmacologia , Ciclopentanos/farmacologia , Oxilipinas/farmacologia , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tamaricaceae/metabolismo , Regulação da Expressão Gênica de Plantas/genética , Regulação da Expressão Gênica de Plantas/fisiologia , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/genética , Plantas Geneticamente Modificadas/genética , Tolerância ao Sal/genética , Tolerância ao Sal/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Tamaricaceae/efeitos dos fármacos
17.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299067

RESUMO

Pancreatic cancer is a fatal disease, and thus its chemoprevention is an important issue. Based on the recent report that patients with allergic diseases have a low risk for pancreatic cancer, we examined the potential chemopreventive effect of anti-allergic agents using a hamster pancreatic carcinogenesis model. Among the three anti-allergic drugs administered, montelukast showed a tendency to suppress the incidence of pancreatic cancer. Further animal study revealed a significantly decreased incidence of pancreatic cancer in the high-dose montelukast group compared with controls. The development of the pancreatic intraepithelial neoplasia lesions was also significantly suppressed. The Ki-67 labeling index was significantly lower in pancreatic carcinomas in the high-dose montelukast group than in controls. In vitro experiments revealed that montelukast suppressed proliferation of pancreatic cancer cells in a dose-dependent manner with decreased expression of phospho-ERK1/2. Montelukast induced G1 phase arrest. Conversely, leukotriene D4 (LTD4), an agonist of CYSLTR1, increased cellular proliferation of pancreatic cancer cells with an accumulation of phospho-ERK1/2. In our cohort, pancreatic ductal adenocarcinoma patients with high CYSLTR1 expression showed a significantly unfavorable clinical outcome compared with those with low expression. Our results indicate that montelukast exerts a chemopreventive effect on pancreatic cancer via the LTD4-CYSLTR1 axis and has potential for treatment of pancreatic carcinogenesis.


Assuntos
Acetatos/farmacologia , Antiasmáticos/farmacologia , Proliferação de Células , Ciclopropanos/farmacologia , Leucotrieno D4/metabolismo , Nitrosaminas/toxicidade , Neoplasias Pancreáticas/tratamento farmacológico , Quinolinas/farmacologia , Receptores de Leucotrienos/metabolismo , Sulfetos/farmacologia , Animais , Carcinógenos/toxicidade , Cricetinae , Humanos , Masculino , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Células Tumorais Cultivadas
18.
Pest Manag Sci ; 77(12): 5382-5395, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34313385

RESUMO

BACKGROUND: Andean lupin (Lupinus mutabilis Sweet) is an important leguminous crop from South America with a high protein content. In Ecuador, lupin yields are severely affected by the infestation of Delia platura larvae on germinating seeds. The application of elicitor molecules with activity against herbivorous insects to control D. platura infestation constitutes an unexplored and promising alternative for chemical insecticides. In this study, methyl jasmonate (MeJA), hexanoic acid, menadione sodium bisulfite, and DL-ß-aminobutyric acid were evaluated for their ability to induce resistance against D. platura in three commercial lupin cultivars. RESULTS: Only seeds pretreated with MeJA significantly impaired insect performance during choice and no-choice assays. Additionally, fitness indicators such as seed germination and growth were not affected by MeJA treatment. To investigate the molecular mechanisms behind the MeJA-mediated resistance, RT-qPCR assays were performed. First, RT-qPCR reference genes were validated, showing that LmUBC was the most stable reference gene. Next, expression analysis over time revealed that MeJA application up-regulated the activity of the jasmonic acid biosynthetic genes LmLOX2 and LmAOS, together with other jasmonate-related defense genes, such as LmTPS1, LmTPS4, LmPI2, LmMBL, LmL/ODC, LmCSD1, and LmPOD. CONCLUSION: This study indicates that MeJA can be used as an environmentally friendly elicitor molecule to protect Andean lupin from D. platura attack without fitness cost. MeJA application induces plant defense responses to insects in Andean lupin that may be modulated by the onset of terpenoid biosynthesis, proteinase inhibitors, lectins, polyamines, and antioxidative enzymes. © 2021 Society of Chemical Industry.


Assuntos
Dípteros , Lupinus , Acetatos/farmacologia , Animais , Ciclopentanos/farmacologia , Regulação da Expressão Gênica de Plantas , Oxilipinas/farmacologia , Sementes
19.
Molecules ; 26(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201111

RESUMO

Recently, the first squaramide-(SA) containing FAP inhibitor-derived radiotracers were introduced. DATA5m.SA.FAPi and DOTA.SA.FAPi with their non-radioactive complexes showed high affinity and selectivity for FAP. After a successful preclinical study with [68Ga]Ga-DOTA.SA.FAPi, the first patient studies were realized for both compounds. Here, we present a new squaramide-containing compound targeting FAP, based on the AAZTA5 chelator 1,4-bis-(carboxylmethyl)-6-[bis-(carboxymethyl)-amino-6-pentanoic-acid]-perhydro-1,4-diazepine. For this molecule (AAZTA5.SA.FAPi), complexation with radionuclides such as gallium-68, scandium-44, and lutetium-177 was investigated, and the in vitro properties of the complexes were characterized and compared with those of DOTA.SA.FAPi. AAZTA5.SA.FAPi and its derivatives labelled with non-radioactive isotopes demonstrated similar excellent inhibitory potencies compared to the previously published SA.FAPi ligands, i.e., sub-nanomolar IC50 values for FAP and high selectivity indices over the serine proteases PREP and DPPs. Labeling with all three radiometals was easier and faster with AAZTA5.SA.FAPi compared to the corresponding DOTA analogue at ambient temperature. Especially, scandium-44 labeling with the AAZTA derivative resulted in higher specific activities. Both DOTA.SA.FAPi and AAZTA5.SA.FAPi showed sufficiently high stability in different media. Therefore, these FAP inhibitor agents could be promising for theranostic approaches targeting FAP.


Assuntos
Acetatos/farmacologia , Azepinas/farmacologia , Fibroblastos/efeitos dos fármacos , Compostos Heterocíclicos com 1 Anel/farmacologia , Proteínas de Membrana/antagonistas & inibidores , Quinina/análogos & derivados , Endopeptidases , Fibroblastos/metabolismo , Radioisótopos de Gálio/farmacologia , Humanos , Ligantes , Lutécio/farmacologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Quinina/farmacologia , Radioisótopos/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Escândio/farmacologia , Serina Endopeptidases/metabolismo
20.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281279

RESUMO

(1) Background: Autophagy, the major cytoplasmic process of substrate turnover, declines with age, contributing to proteostasis decline, accumulation of harmful protein aggregates, damaged mitochondria and to ROS production. Accordingly, abnormalities in the autophagic flux may contribute to many different pathophysiological conditions associated with ageing, including neurodegeneration. Recent data have shown that extra-virgin olive oil (EVOO) polyphenols stimulate cell defenses against plaque-induced neurodegeneration, mainly, through autophagy induction. (2) Methods: We carried out a set of in vitro experiments on SH-SY5Y human neuroblastoma cells exposed to toxic Aß1-42 oligomers to investigate the molecular mechanisms involved in autophagy activation by two olive oil polyphenols, oleuropein aglycone (OleA), arising from the hydrolysis of oleuropein (Ole), the main polyphenol found in olive leaves and drupes and its main metabolite, hydroxytyrosol (HT). (3) Results: Our data show that the mixture of the two polyphenols activates synergistically the autophagic flux preventing cell damage by Aß1-42 oligomers., in terms of ROS production, and impairment of mitochondria. (4) Conclusion: Our results support the idea that EVOO polyphenols act synergistically in autophagy modulation against neurodegeneration. These data confirm and provide the rationale to consider these molecules, alone or in combination, as promising candidates to contrast ageing-associated neurodegeneration.


Assuntos
Doença de Alzheimer/dietoterapia , Azeite de Oliva/farmacologia , Polifenóis/farmacologia , Acetatos/administração & dosagem , Acetatos/química , Acetatos/farmacologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Autofagia/efeitos dos fármacos , Linhagem Celular , Monoterpenos Ciclopentânicos/administração & dosagem , Monoterpenos Ciclopentânicos/química , Monoterpenos Ciclopentânicos/farmacologia , Dieta Mediterrânea , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Neurológicos , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Degeneração Neural/prevenção & controle , Neurônios/efeitos dos fármacos , Neurônios/patologia , Azeite de Oliva/administração & dosagem , Azeite de Oliva/química , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/toxicidade , Álcool Feniletílico/administração & dosagem , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Polifenóis/administração & dosagem , Polifenóis/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Piranos/administração & dosagem , Piranos/química , Piranos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Ubiquitina/metabolismo
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