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1.
Open Biol ; 13(5): 220355, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37132222

RESUMO

Papaver somniferum L. (Family: Papaveraceae) is a species well known for its diverse alkaloids (100 different benzylisoquinoline alkaloids (BIAs)). L-tyrosine serves as a precursor of several specific metabolites like BIAs. It has been used as an antitussive and potent analgesic to alleviate mild to extreme pain since ancient times. The extraction of pharmaceutically important alkaloids like morphine and codeine from poppy plant reflects the need for the most suitable and standard methods. Several analytical and extraction techniques have been reported in open literature for morphine, codeine and other important alkaloids which play a vital function in drug development and drug discovery. Many studies suggest that opioids are also responsible for adverse effects or secondary complications like dependence and withdrawal. In recent years, opium consumption and addiction are the most important risk factors. Many evidence-based reviews suggest that opium consumption is directly linked or acts as a risk factor for different cancers. In this review, we highlight significant efforts related to research which have been done over the past 5 decades and the complete information on Papaver somniferum including its phytochemistry, pharmacological actions, biosynthetic pathways and analytical techniques of opium alkaloid extraction and the link between opium consumption and cancer-related updates.


Assuntos
Alcaloides , Benzilisoquinolinas , Neoplasias , Papaver , Ópio/efeitos adversos , Ópio/metabolismo , Alcaloides/farmacologia , Alcaloides/metabolismo , Benzilisoquinolinas/farmacologia , Benzilisoquinolinas/metabolismo , Papaver/metabolismo , Codeína/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Derivados da Morfina/metabolismo
2.
Mar Drugs ; 21(4)2023 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-37103397

RESUMO

Marine sponges are multicellular and primitive animals that potentially represent a wealthy source of novel drugs. The genus Acanthella (family Axinellidae) is renowned to produce various metabolites with various structural characteristics and bioactivities, including nitrogen-containing terpenoids, alkaloids, and sterols. The current work provides an up-to-date literature survey and comprehensive insight into the reported metabolites from the members of this genus, as well as their sources, biosynthesis, syntheses, and biological activities whenever available. In the current work, 226 metabolites have been discussed based on published data from the period from 1974 to the beginning of 2023 with 90 references.


Assuntos
Alcaloides , Produtos Biológicos , Poríferos , Animais , Poríferos/química , Alcaloides/farmacologia , Alcaloides/metabolismo , Terpenos/química , Nitrogênio/metabolismo , Produtos Biológicos/química
3.
Molecules ; 28(7)2023 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-37049942

RESUMO

Meleagrin and oxaline, which belong to the roquefortine alkaloids with a unique dihydroindole spiroamide framework, have significant bioactivities, especially tumor cell inhibitory activity. In order to discover the requefortine alkaloids, Penicillium sp. OUCMDZ-1435 was fished and identified from marine fungi using molecular probe technology. Meleagrin (1) and oxaline (2) were isolated from it. In addition, we first reported that compounds 1 and 2 could effectively inhibit the proliferation and metastasis of the human HepG2 cell and induce HepG2 cell apoptosis and cell cycle arrest in the G2/M phase. Additionally, the fermentation of Meleagrin (1) was optimized to increase its yield to 335 mg/L. These results provided bioactive inspiration and fungus resources for roquefortine alkaloid development.


Assuntos
Alcaloides , Penicillium , Humanos , Penicillium/metabolismo , Fermentação , Indóis/farmacologia , Indóis/metabolismo , Alcaloides/farmacologia , Alcaloides/metabolismo
4.
Int J Mol Sci ; 24(7)2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-37047398

RESUMO

Inflammatory bowel disease (IBD) refers to chronic intestinal immune-mediated diseases including two main disease manifestations: ulcerative colitis (UC) and Crohn's disease (CD). Epidemiological, clinical, and preclinical evidence has highlighted the potential anti-inflammatory properties of naturally occurring alkaloids. In the present study, we investigated the potential anti-inflammatory activities of the tobacco alkaloids nicotine and anatabine in a dextran sulfate sodium (DSS)-induced UC mouse model with a fully humanized immune system. Our results show that nicotine significantly reduced all acute colitis symptoms and improved colitis-specific endpoints, including histopathologically assessed colon inflammation, tissue damage, and mononuclear cell infiltration. The tobacco alkaloid anatabine showed similar effectiveness trends, although they were generally weaker or not significant. Gene expression analysis in the context of biological network models of IBD further pinpointed a possible mechanism by which nicotine attenuated DSS-induced colitis in humanized mice. The current study enables further investigation of possible molecular mechanisms by which tobacco alkaloids attenuate UC symptoms.


Assuntos
Alcaloides , Antineoplásicos , Colite Ulcerativa , Colite , Doenças Inflamatórias Intestinais , Animais , Camundongos , Tabaco/efeitos adversos , Nicotina/efeitos adversos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Modelos Animais de Doenças , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/uso terapêutico , Alcaloides/farmacologia , Alcaloides/metabolismo , Sistema Imunitário/metabolismo , Sulfato de Dextrana/toxicidade , Camundongos Endogâmicos C57BL , Colo/metabolismo
5.
Metab Eng ; 77: 162-173, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37004909

RESUMO

Sacred lotus (Nelumbo nucifera) has been utilized as a food, medicine, and spiritual symbol for nearly 3000 years. The medicinal properties of lotus are largely attributed to its unique profile of benzylisoquinoline alkaloids (BIAs), which includes potential anti-cancer, anti-malarial and anti-arrhythmic compounds. BIA biosynthesis in sacred lotus differs markedly from that of opium poppy and other members of the Ranunculales, most notably in an abundance of BIAs possessing the (R)-stereochemical configuration and the absence of reticuline, a major branchpoint intermediate in most BIA producers. Owing to these unique metabolic features and the pharmacological potential of lotus, we set out to elucidate the BIA biosynthesis network in N. nucifera. Here we show that lotus CYP80G (NnCYP80G) and a superior ortholog from Peruvian nutmeg (Laurelia sempervirens; LsCYP80G) stereospecifically convert (R)-N-methylcoclaurine to the proaporphine alkaloid glaziovine, which is subsequently methylated to pronuciferine, the presumed precursor to nuciferine. While sacred lotus employs a dedicated (R)-route to aporphine alkaloids from (R)-norcoclaurine, we implemented an artificial stereochemical inversion approach to flip the stereochemistry of the core BIA pathway. Exploiting the unique substrate specificity of dehydroreticuline synthase from common poppy (Papaver rhoeas) and pairing it with dehydroreticuline reductase enabled de novo synthesis of (R)-N-methylcoclaurine from (S)-norcoclaurine and its subsequent conversion to pronuciferine. We leveraged our stereochemical inversion approach to also elucidate the role of NnCYP80A in sacred lotus metabolism, which we show catalyzes the stereospecific formation of the bis-BIA nelumboferine. Screening our collection of 66 plant O-methyltransferases enabled conversion of nelumboferine to liensinine, a potential anti-cancer bis-BIA from sacred lotus. Our work highlights the unique benzylisoquinoline metabolism of N. nucifera and enables the targeted overproduction of potential lotus pharmaceuticals using engineered microbial systems.


Assuntos
Alcaloides , Benzilisoquinolinas , Nelumbo , Compostos de Espiro , Nelumbo/genética , Nelumbo/química , Nelumbo/metabolismo , Alcaloides/química , Alcaloides/metabolismo , Alcaloides/farmacologia , Benzilisoquinolinas/metabolismo , Compostos de Espiro/metabolismo
6.
Int J Mol Sci ; 24(8)2023 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-37108206

RESUMO

The present work focuses on in vitro cultures of Ruta montana L. in temporary immersion PlantformTM bioreactors. The main aim of the study was to evaluate the effects of cultivation time (5 and 6 weeks) and different concentrations (0.1-1.0 mg/L) of plant growth and development regulators (NAA and BAP) on the increase in biomass and the accumulation of secondary metabolites. Consequently, the antioxidant, antibacterial, and antibiofilm potentials of methanol extracts obtained from the in vitro-cultured biomass of R. montana were evaluated. High-performance liquid chromatography analysis was performed to characterize furanocoumarins, furoquinoline alkaloids, phenolic acids, and catechins. The major secondary metabolites in R. montana cultures were coumarins (maximum total content of 1824.3 mg/100 g DM), and the dominant compounds among them were xanthotoxin and bergapten. The maximum content of alkaloids was 561.7 mg/100 g DM. Concerning the antioxidant activity, the extract obtained from the biomass grown on the 0.1/0.1 LS medium variant, with an IC50 0.90 ± 0.03 mg/mL, showed the best chelating ability among the extracts, while the 0.1/0.1 and 0.5/1.0 LS media variants showed the best antibacterial (MIC range 125-500 µg/mL) and antibiofilm activity against resistant Staphylococcus aureus strains.


Assuntos
Alcaloides , Staphylococcus aureus Resistente à Meticilina , Ruta , Ruta/química , Ruta/metabolismo , Imersão , Montana , Alcaloides/farmacologia , Alcaloides/metabolismo , Reatores Biológicos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Extratos Vegetais/química , Antibacterianos/farmacologia , Antibacterianos/metabolismo
7.
Mar Drugs ; 21(3)2023 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-36976216

RESUMO

Two new alkaloids, streptopyrroles B and C (1 and 2), were discovered through a chemical investigation of the ethyl acetate (EtOAc) extract from a marine-derived actinomycete, Streptomyces zhaozhouensis, along with four known analogs (3-6). The structures of the new compounds were elucidated by spectroscopic analysis (HR-ESIMS, 1D, and 2D NMR) and a comparison of their experimental data with literature values. The new compounds were evaluated for their antimicrobial activity by standard broth dilution assay, and the tested compounds showed significant activity against Gram-positive bacteria with minimum inhibitory concentration (MIC) values ranging from 0.7 to 2.9 µM, and kanamycin was used as a positive control with MIC values ranging from <0.5 to 4.1 µM. Additionally, 1, 3, and 5 were evaluated for their cytotoxicity against six tumor cell lines by sulforhodamine B (SRB) assay, and these compounds displayed cytotoxic activities against all the tested cell lines, with concentration causing 50% cell growth inhibition (GI50) values ranging from 4.9 to 10.8 µM, while a positive control, adriamycin, showed GI50 values of 0.13-0.17 µM.


Assuntos
Actinobacteria , Alcaloides , Anti-Infecciosos , Antineoplásicos , Antibacterianos/química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/metabolismo , Antineoplásicos/química , Espectroscopia de Ressonância Magnética , Actinobacteria/metabolismo , Alcaloides/farmacologia , Alcaloides/metabolismo , Testes de Sensibilidade Microbiana
8.
Molecules ; 28(5)2023 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-36903506

RESUMO

Alzheimer's is the most common cause of dementia worldwide and seriously affects patients' daily tasks. Plant endophytic fungi are known for providing novel and unique secondary metabolites with diverse activities. This review focuses primarily on the published research regarding anti-Alzheimer's natural products derived from endophytic fungi between 2002 and 2022. Following a thorough review of the literature, 468 compounds with anti-Alzheimer's-related activities are reviewed and classified based on their structural skeletons, primarily including alkaloids, peptides, polyketides, terpenoids, and sterides. The classification, occurrences, and bioactivities of these natural products from endophytic fungi are summarized in detail. Our results provide a reference on endophytic fungi natural products that may assist in the development of new anti-Alzheimer's compounds.


Assuntos
Alcaloides , Produtos Biológicos , Policetídeos , Humanos , Produtos Biológicos/química , Endófitos/química , Fungos/química , Policetídeos/química , Alcaloides/metabolismo
9.
Nat Chem ; 15(4): 560-568, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36894702

RESUMO

Ribosomally synthesized and post-translationally modified peptide natural products have provided many highly unusual scaffolds. This includes the intriguing alkaloids crocagins, which possess a tetracyclic core structure and whose biosynthesis has remained enigmatic. Here we use in vitro experiments to demonstrate that three proteins, CgnB, CgnC and CgnE, are sufficient for the production of the hallmark tetracyclic crocagin core from the precursor peptide CgnA. The crystal structures of the homologues CgnB and CgnE reveal them to be the founding members of a peptide-binding protein family and allow us to rationalize their distinct functions. We further show that the hydrolase CgnD liberates the crocagin core scaffold, which is subsequently N-methylated by CgnL. These insights allow us to propose a biosynthetic scheme for crocagins. Bioinformatic analyses based on these data led to the discovery of related biosynthetic pathways that may provide access to a structurally diverse family of peptide-derived pyrroloindoline alkaloids.


Assuntos
Proteínas , Ligação Proteica , Proteínas/química , Proteínas/metabolismo , Alcaloides/química , Alcaloides/metabolismo , Peptídeos Cíclicos/química , Peptídeos Cíclicos/metabolismo , Zinco/química , Zinco/metabolismo , Multimerização Proteica , Modelos Moleculares , Estrutura Terciária de Proteína , Estrutura Quaternária de Proteína , Biocatálise
10.
Biomed Pharmacother ; 158: 114190, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36916441

RESUMO

Securinega alkaloids are indolizidine alkaloids extracted from the leaf and root of an Asian plant, Securinega suffruticosa. Since its discovery in 1956 by Russian scientists, numerous studies have been conducted on securinega alkaloids and their derivatives as bioactive agents. In this review, published work on the bioactivities and the mechanism of action of securinega alkaloids and their derivatives is addressed. References were obtained through for example, the Web of Science, Science Direct, Pubmed and Google Scholar. Research into the synthesis of securinega alkaloids and their derivatives lacking activity assessment has been excluded. Comprehensive reviews show that securinega alkaloids and their derivatives exhibit a wide range of activities among which antineoplastic activity and nervous system related activity were reported although the mechanisms of action remain in part unknown. The other activities such as induction of differentiation, reversal of multi-drug resistance, cardiovascular system related activity, anti-inflammatory, adjuvant agent and anti-pathogenic activity are also reviewed. We found that modification at the C12, C14, and C15 sites on securinine improves the antitumor activity, while derivatives in which a bivalent mimetic is linked to the C15 site is beneficial for differentiation induction activity and reversal of P-glycoprotein mediated drug resistance. The most related pathways involved in the bioactivity of securinega alkaloids and their derivatives are JAK/STAT, PI3K/AKT/mTOR and MAPK. A perspective and expectation concerning the research of securinega alkaloids is presented at the end of this article. This review indicates directions around which constant endeavor could be valuable for researchers in the near future.


Assuntos
Alcaloides , Securinega , Fosfatidilinositol 3-Quinases , Alcaloides/farmacologia , Alcaloides/metabolismo
11.
New Phytol ; 238(4): 1351-1361, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36727281

RESUMO

Heritable fungal endosymbiosis is underinvestigated in plant biology and documented in only three plant families (Convolvulaceae, Fabaceae, and Poaceae). An estimated 40% of morning glory species in the tribe Ipomoeeae (Convolvulaceae) have associations with one of two distinct heritable, endosymbiotic fungi (Periglandula and Chaetothyriales) that produce the bioactive metabolites ergot alkaloids, indole diterpene alkaloids, and swainsonine, which have been of interest for their toxic effects on animals and potential medical applications. Here, we report the occurrence of ergot alkaloids, indole diterpene alkaloids, and swainsonine in the Convolvulaceae; and the fungi that produce them based on synthesis of previous studies and new indole diterpene alkaloid data from 27 additional species in a phylogenetic, geographic, and life-history context. We find that individual morning glory species host no more than one metabolite-producing fungal endosymbiont (with one possible exception), possibly due to costs to the host and overlapping functions of the alkaloids. The symbiotic morning glory lineages occur in distinct phylogenetic clades, and host species have significantly larger seed size than nonsymbiotic species. The distinct and widely distributed endosymbiotic relationships in the morning glory family and their alkaloids provide an accessible study system for understanding heritable plant-fungal symbiosis evolution and their potential functions for host plants.


Assuntos
Alcaloides , Convolvulaceae , Alcaloides de Claviceps , Ipomoea , Animais , Convolvulaceae/metabolismo , Convolvulaceae/microbiologia , Swainsonina/metabolismo , Filogenia , Ipomoea/genética , Ipomoea/metabolismo , Ipomoea/microbiologia , Alcaloides de Claviceps/metabolismo , Alcaloides/metabolismo , Alcaloides Diterpenos
12.
Microb Cell Fact ; 22(1): 23, 2023 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-36737755

RESUMO

Benzylisoquinoline alkaloids (BIAs) are a type of secondary metabolite with clinical application value. (S)-stylopine is a special BIA which contains methylenedioxy bridge structures. CYP719As could catalyze the methylenedioxy bridge-formation on the A or D rings of protoberberine alkaloids, while displaying significant substrate regiospecificity. To explore the substrate preference of CYP719As, we cloned and identified five CyCYP719A candidates from Corydalis yanhusuo. Two CyCYP719As (CyCYP719A39 and CyCYP719A42) with high catalytic efficiency for the methylenedioxy bridge-formation on the D or A rings were characterized, respectively. The residues (Leu 294 for CyCYP719A42 and Asp 289 for CyCYP719A39) were identified as the key to controlling the regioselectivity of CYP719As affecting the methylenedioxy bridge-formation on the A or D rings by homology modeling and mutation analysis. Furthermore, for de novo production of BIAs, CyCYP719A39, CyCYP719A42, and their mutants were introduced into the (S)-scoulerine-producing yeast to produce 32 mg/L (S)-stylopine. These results lay a foundation for understanding the structure-function relationship of CYP719A-mediated methylenedioxy bridge-formation and provide yeast strains for the BIAs production by synthetic biology.


Assuntos
Alcaloides , Benzilisoquinolinas , Benzilisoquinolinas/metabolismo , Saccharomyces cerevisiae/metabolismo , Alcaloides/metabolismo
13.
J Plant Res ; 136(3): 397-412, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36809401

RESUMO

Under natural conditions plants are generally subjected to complex scenarios of combined or sequential environmental stresses. Among the various components of plant biochemistry modulated by abiotic variables, a pivotal role is played by antioxidant systems, including specialized metabolites and their interaction with central pathways. To help address this knowledge gap, a comparative analysis of metabolic changes in leaf tissues of the alkaloid accumulating plant Psychotria brachyceras Müll Arg. under individual, sequential, and combined stress conditions was carried out. Osmotic and heat stresses were evaluated. Protective systems (accumulation of the major antioxidant alkaloid brachycerine, proline, carotenoids, total soluble protein, and activity of the enzymes ascorbate peroxidase and superoxide dismutase) were measured in conjunction with stress indicators (total chlorophyll, ChA/ChB ratio, lipid peroxidation, H2O2 content and electrolyte leakage). Metabolic responses had a complex profile in sequential and combined stresses compared to single ones, being also modified over time. Different stress application schemes affected alkaloid accumulation in distinct ways, exhibiting similar profile to proline and carotenoids, constituting a complementary triad of antioxidants. These complementary non-enzymatic antioxidant systems appeared to be essential for mitigating stress damage and re-establishing cellular homeostasis. The data herein provides clues that may aid the development of a key component framework of stress responses and their appropriate balance to modulate tolerance and yield of target specialized metabolites.


Assuntos
Alcaloides , Psychotria , Antioxidantes/metabolismo , Psychotria/química , Psychotria/metabolismo , Peróxido de Hidrogênio/metabolismo , Alcaloides/metabolismo , Carotenoides/análise , Carotenoides/metabolismo , Folhas de Planta/metabolismo , Prolina/análise , Prolina/metabolismo
14.
Molecules ; 28(3)2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36771067

RESUMO

The presence of endophytes in plants is undeniable, but how significant their involvement is in the host plant biosynthetic pathways is still unclear. The results reported from fungicide treatments in plants varied. Fungicide treatment in Taxus was found to decrease the taxol content. In Ipomoea asarifolia, Pronto Plus and Folicur treatments coincided with the disappearance of ergot alkaloids from the plant. In Narcissus pseudonarcissus cv. Carlton, a mixture of fungicide applications decreased the alkaloids concentration and altered the carbohydrate metabolism. Jacobaea plants treated with Folicur reduced the pyrrolizidine alkaloids content. There have not been any studies into the involvement of endophytic fungi on alkaloids production of Catharanthus roseus until now. Though there is a report on the isolation of the endophytic fungi, Fusarium oxysporum from C. roseus, which was reported to produce vinblastine and vincristine in vitro. To detect possible collaborations between these two different organisms, fungicides were applied to suppress the endophytic fungi in seedlings and then measure the metabolomes by 1HNMR and HPLC analysis. The results indicate that endophytic fungi were not directly involved in alkaloids biosynthesis. Treatment with fungicides influenced both the primary and secondary metabolism of C. roseus. The systemic fungicides Pronto Plus and Folicur caused an increase in loganin and secologanin levels. In contrast, control samples had higher level of catharanthine and vindoline. This means that fungicide treatments cause changes in plant secondary metabolism.


Assuntos
Alcaloides , Antineoplásicos , Catharanthus , Fungicidas Industriais , Alcaloides de Triptamina e Secologanina , Plântula/metabolismo , Fungicidas Industriais/farmacologia , Fungicidas Industriais/metabolismo , Catharanthus/química , Alcaloides/metabolismo , Vincristina/metabolismo , Antineoplásicos/metabolismo , Alcaloides de Triptamina e Secologanina/metabolismo
15.
Fitoterapia ; 166: 105433, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36646355

RESUMO

By adding natural amino acids into the medium as sole nitrogen source, twenty-four compounds, including two new alkaloids lentinuses A-B (1-2) with a rare oxazinone core in marine natural products, one new natural product 3-acetamido-4-phenylfurazan (3), 9ß-ergosterol (22) were firstly discovered from a marine fungus, and twenty known compounds (4-21, 23-24) were isolated from the marine-derived fungus Lentinus sajor-caju. The chemical structures of all these compounds were elucidated by HRMS, NMR spectroscopy and X-ray diffraction. Compounds 1-24 were evaluated for their inhibitory activity against TGF-ß1-induced collagen accumulation in human fetal lung fibroblasts (HFL1). Compounds 2, 3, 12, 22, and 23 showed potent activity against TGF-ß1-induced collagen accumulation and low toxicity to HFL1 cells. The binding mode of lentinus B (2) with TGF-ß1 receptor was then performed by using Schrödinger software, and the result showed that lentinus B possesses a strong binding force such as hydrogen bonding and hydrophobic interactions to the protein, which may provide a theoretical basis to design more potent anti-fibrotic drugs in the future.


Assuntos
Alcaloides , Lentinula , Humanos , Fator de Crescimento Transformador beta1/metabolismo , Estrutura Molecular , Lentinula/química , Lentinula/metabolismo , Colágeno/metabolismo , Alcaloides/farmacologia , Alcaloides/metabolismo , Fibrose
16.
Pharm Biol ; 61(1): 135-143, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36617895

RESUMO

CONTEXT: Alkaloid-enriched extract of Huperzia serrata (Thunb.) Trevis (Lycopodiaceae) (HsAE) can potentially be used to manage neuronal disorders. OBJECTIVE: This study determines the anti-neuroinflammatory effects of HsAE on lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and the underlying mechanisms. MATERIALS AND METHODS: BV-2 cells were pre- or post-treated with different concentrations of HsAE (25-150 µg/mL) for 30 min before or after LPS induction. Cell viability was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and no cytotoxicity was found. Nitric oxide (NO) concentration was determined using Griess reagent. The levels of prostaglandin E2 (PGE2), tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 were determined using enzyme-linked immunosorbent assay. The levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 and the phosphorylation of mitogen-activated protein kinase (MAPK) were analyzed using western blotting. RESULTS: HsAE reduced LPS-induced NO production with half-maximal inhibitory concentration values of 99.79 and 92.40 µg/mL at pre- and post-treatment, respectively. Pre-treatment with HsAE at concentrations of 50, 100, and 150 µg/mL completely inhibited the secretion of PGE2, TNF-α, IL-6, and IL-1ß compared to post-treatment with HsAE. This suggests that prophylactic treatment is better than post-inflammation treatment. HsAE decreased the expression levels of iNOS and COX-2 and attenuated the secretion of pro-inflammatory factors by downregulating the phosphorylation of p38 and extracellular signal-regulated protein kinase in the MAPK signaling pathway. DISCUSSION AND CONCLUSIONS: HsAE exerts anti-neuroinflammatory effects on LPS-stimulated BV-2 cells, suggesting that it may be a potential candidate for the treatment of neuroinflammation in neurodegenerative diseases.


Assuntos
Alcaloides , Huperzia , Lipopolissacarídeos/farmacologia , Huperzia/metabolismo , Interleucina-6/metabolismo , Doenças Neuroinflamatórias , Dinoprostona/metabolismo , Microglia , Fator de Necrose Tumoral alfa/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Alcaloides/farmacologia , Alcaloides/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo
17.
Molecules ; 28(2)2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36677781

RESUMO

This study aimed to examine the influence of the addition of a precursor (phenylalanine) on the accumulation of secondary metabolites in agitated shoot cultures of Ruta graveolens. Cultures were grown on Linsmaier and Skoog (LS) medium, with plant growth regulators (0.1 mg/L α-naphthaleneacetic acid-NAA-and 0.1 mg/L 6-benzylaminopurine-BAP). Phenylalanine was added to the cultures at a concentration of 1.25 g/L after 4 and 5 weeks of growth cycles. Biomass was collected after 2, 4, and 7 days of precursor addition. Both control and experimental cultures had the same secondary metabolites accumulated. Using the HPLC method, linear furanocoumarins (bergapten, isoimperatorin, isopimpinellin, psoralen, and xanthotoxin), furoquinoline alkaloids (γ-fagarine, 7-isopentenyloxy-γ-fagarine, and skimmianine), and catechin were detected and quantified in the methanolic extracts. In turn, phenolic acids, such as gallic acid, protocatechuic acid, p-hydroxybenzoic acid, syringic acid, p-coumaric acid, and ferulic acid were detected in hydrolysates. The production of phenolic acids and catechin (1.5-fold) was significantly increased by the addition of precursor, while there was no significant effect on the production of coumarins and alkaloids. The highest total content of phenolic acids (109 mg/100 g DW) was obtained on the second day of phenylalanine addition (the fourth week of growth cycles). The dominant phenolic compounds were p-coumaric acid (maximum content 64.3 mg/100 g DW) and ferulic acid (maximum content 35.6 mg/100 g DW). In the case of catechins, the highest total content (66 mg/100 g DW) was obtained on the third day of precursor addition (the fourth week of growth cycles). This study is the first to document the effect of feeding the culture medium with phenylalanine on the accumulation of bioactive metabolites in in vitro cultures of R. graveolens.


Assuntos
Alcaloides , Catequina , Ruta , Fenilalanina/metabolismo , Catequina/metabolismo , Alcaloides/metabolismo
18.
Molecules ; 27(22)2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36431969

RESUMO

One of the most common diseases affecting people and leading to high morbidity is kidney injury. The alleviation of inflammation and apoptosis is considered a potential therapeutic approach for kidney injury. Sophocarpine (SOP), a tetracyclic quinolizidine alkaloid, exhibits various beneficial biological properties. To investigate the effects of SOP on isoproterenol (ISO)-induced kidney injury, we randomly divided mice into four groups: Control, ISO, ISO+SOP (20 mg/kg) and ISO+SOP (40 mg/kg). SOP was administered intraperitoneally to the mice over two weeks, accompanied by intraperitoneal stimulation of ISO (10 mg/kg) for another four weeks. After the mice were sacrificed, several methods such as ELISA, staining (H&E, TUNEL, DHE and Masson) and Western blotting were applied to detect the corresponding indicators. The kidney injury serum biomarkers SCr and BUN increased after the ISO challenge, while this effect was reversed by treatment with SOP. Pathological changes induced by ISO were also reversed by treatment with SOP in the staining. The inflammatory cytokines IL-ß, IL-6, TNF-α, MCP-1 and NLRP3 increased after the challenge with ISO, while they were decreased by treatment with SOP. The apoptotic proteins cleaved-caspase-3 and Bax increased, while Bcl-2 decreased, after the challenge with ISO, and these effects were reversed by treatment with SOP. The antioxidant proteins SOD-1 and SOD-2 decreased after being stimulated by ISO, while they increased after the treatment with SOP. The fibrotic proteins collagen I, collagen III, α-SMA, fibronectin, MMP-2 and MMP-9 increased after the challenge with ISO, while they decreased after the treatment with SOP. We further discovered that the TLR-4/NF-κB and TGF-ß1/Smad3 signaling pathways were suppressed, while the Nrf2/HO-1 signaling pathway was activated. In summary, SOP could alleviate ISO-induced kidney injury by inhibiting inflammation, apoptosis, oxidative stress and fibrosis. The molecular mechanisms were suppression of the TLR-4/NF-κB and TGF-ß1/Smad3 signaling pathways and activation of the Nrf2/HO-1 signaling pathway, indicating that SOP might serve as a novel therapeutic strategy for kidney injury.


Assuntos
Alcaloides , Fator 2 Relacionado a NF-E2 , Camundongos , Animais , Isoproterenol/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Estresse Oxidativo , Fibrose , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Alcaloides/metabolismo , Apoptose , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Rim/metabolismo
19.
Toxins (Basel) ; 14(11)2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36356021

RESUMO

Curcin and Curcin C, both of the ribosome-inactivating proteins of Jatropha curcas, have apparent inhibitory effects on the proliferation of osteosarcoma cell line U20S. However, the inhibitory effect of the latter is 13-fold higher than that of Curcin. The mechanism responsible for the difference has not been studied. This work aimed to understand and verify whether there are differences in entry efficiency and pathway between them using specific endocytosis inhibitors, gene silencing, and labeling techniques such as fluorescein isothiocyanate (FITC) labeling. The study found that the internalization efficiency of Curcin C was twice that of Curcin for U2OS cells. More than one entering pathway was adopted by both of them. Curcin C can enter U2OS cells through clathrin-dependent endocytosis and macropinocytosis, but clathrin-dependent endocytosis was not an option for Curcin. The low-density lipoprotein receptor-related protein 1 (LRP1) was found to mediate clathrin-dependent endocytosis of Curcin C. After LRP1 silencing, there was no significant difference in the 50% inhibitory concentration (IC50) and endocytosis efficiency between Curcin and Curcin C on U2OS cells. These results indicate that LRP1-mediated endocytosis is specific to Curcin C, thus leading to higher U2OS endocytosis efficiency and cytotoxicity than Curcin.


Assuntos
Alcaloides , Jatropha , Osteossarcoma , Toxinas Biológicas , Humanos , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia , Jatropha/genética , Jatropha/metabolismo , Proteínas Inativadoras de Ribossomos/metabolismo , Toxinas Biológicas/metabolismo , Alcaloides/metabolismo , Clatrina/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
20.
Int J Mol Sci ; 23(21)2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36362268

RESUMO

Diterpene alkaloids (DAs) are characteristic compounds in Aconitum, which are classified into four skeletal types: C18, C19, C20, and bisditerpenoid alkaloids. C20-DAs are thought to be the precursor of the other types. Their biosynthetic pathway, however, is largely unclear. Herein, we combine metabolomics and transcriptomics to unveil the methyl jasmonate (MJ) inducible biosynthesis of DAs in the sterile seedling of A. gymnandrum, the only species in the Subgenus Gymnaconitum (Stapf) Rapaics. Target metabolomics based on root and aerial portions identified 51 C19-DAs and 15 C20-DAs, with 40 inducible compounds. The highest content of C20-DA atisine was selected for further network analysis. PacBio Isoform sequencing integrated with RNA sequencing not only provided the full-length transcriptome but also their response to induction, revealing 1994 genes that exhibited up-regulated expression. Further, 38 genes involved in terpenoid biosynthesis were identified, including 7 diterpene synthases. In addition to the expected function of the four diterpene synthases, AgCPS5 was identified to be a new ent-8,13-CPP synthase in Aconitum and could also combine with AgKSL1 to form the C20-DAs precursor ent-atiserene. Combined with multiple network analyses, six CYP450 and seven 2-ODD genes predicted to be involved in the biosynthesis of atisine were also identified. This study not only sheds light on diterpene synthase evolution in Aconitum but also provides a rich dataset of full-length transcriptomes, systemic metabolomes, and gene expression profiles, setting the groundwork for further investigation of the C20-DAs biosynthesis pathway.


Assuntos
Aconitum , Alcaloides , Diterpenos , Aconitum/genética , Aconitum/metabolismo , Transcriptoma , Alcaloides/metabolismo , Diterpenos/metabolismo , Vias Biossintéticas/genética
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