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1.
Toxins (Basel) ; 14(7)2022 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-35878204

RESUMO

Funicone-like compounds are a homogeneous group of polyketides that, so far, have only been reported as fungal secondary metabolites. In particular, species in the genus Talaromyces seem to be the most typical producers of this group of secondary metabolites. The molecular structure of funicone, the archetype of these products, is characterized by a γ-pyrone ring linked through a ketone group to a α-resorcylic acid nucleus. This review provides an update on the current knowledge on the chemistry of funicone-like compounds, with special emphasis on their classification, occurrence, and diverse biological activities. In addition, their potential relevance as mycotoxins is discussed.


Assuntos
Penicillium , Policetídeos , Talaromyces , Penicillium/metabolismo , Policetídeos/metabolismo , Pironas/metabolismo , Pironas/farmacologia , Talaromyces/metabolismo
2.
An Acad Bras Cienc ; 94(2): e20200520, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35703688

RESUMO

Kavain is one of the main kavalactones of Piper methysticum (Piperaceae) with anxiolytic, analgesic, and antioxidant activities. Therefore, the aim of the study was to evaluate the cytotoxic, mutagenic, and antimutagenic potential of kavain in Allium cepa cells. Roots of A. cepa were transferred to the negative (2% acetone) and positive (10 µg/mL of Methylmethanesulfonate, MMS) controls and to the concentrations of kavain (32, 64 and 128 µg/mL) for 48 h. A total of 5,000 meristematic cells were analyzed under an optical microscope to determine the mitotic index, mean number of chromosomal alterations and percentage of damage reduction. Data were analyzed by Kruskal-Wallis test (p <0.05). All concentrations of kavain were not cytotoxic and did not show significant chromosomal changes when compared to 2% acetone. Kavain showed a cytoprotective effect in the pre (128 µg/mL) and in the post-treatment (32 and 64 µg/mL) and reduced damage against the mutagenic action of MMS in all concentrations of the pre and simultaneous and at the highest of post (128 µg/mL). Kavain promoted a significant reduction in micronuclei, nuclear buds and chromosomal losses in relation to MMS. The observed data indicate the importance of kavain for the inhibition of damage and chemoprevention.


Assuntos
Acetona , Cebolas , Acetona/farmacologia , Aberrações Cromossômicas , Meristema , Mutagênicos/toxicidade , Raízes de Plantas , Pironas/farmacologia
3.
Chem Biodivers ; 19(8): e202200491, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35707944

RESUMO

Chemical investigation of the endophytic fungus Phomopsis asparagi LSLYZ-87 cultured on PDB medium led to the isolation of two new pyrone derivatives, phomasparapyrone A (1), and phomasparapyrone B (2), together with the known kojic acid (3). Their planar structures were connected through 1D and 2D NMR spectroscopic data. And the stereo structures of 1 and 2 were defined by comparison of the experimental ECD spectra to calculated one. All isolates were evaluated for their anti-neuroinflammatory activities. Among them, compound 2 showed moderate inhibition on NO accumulation induced by LPS on BV-2 cells in a dose dependent manner at 30, 40 and 50 µM, and without cytotoxicity in a concentration of 50.0 µM.


Assuntos
Fungos , Pironas , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Phomopsis , Pironas/química , Pironas/farmacologia
4.
Mar Drugs ; 20(5)2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35621945

RESUMO

Culturing ascidian-derived fungus Amphichorda felina SYSU-MS7908 under standard laboratory conditions mainly yielded meroterpenoid, and nonribosomal peptide-type natural products. We sequenced the genome of Amphichorda felina SYSU-MS7908 and found 56 biosynthetic gene clusters (BGCs) after bioinformatics analysis, suggesting that the majority of those BGCSs are silent. Here we report our genome mining effort on one cryptic BGC by heterologous expression in Aspergillus oryzae NSAR1, and the identification of two new α-pyrone derivatives, amphichopyrone A (1) and B (2), along with a known compound, udagawanone A (3). Anti-inflammatory activities were performed, and amphichopyrone A (1) and B (2) displayed potent anti-inflammatory activity by inhibiting nitric oxide (NO) production in RAW264.7 cells with IC50 values 18.09 ± 4.83 and 7.18 ± 0.93 µM, respectively.


Assuntos
Beauveria , Produtos Biológicos , Urocordados , Animais , Beauveria/metabolismo , Produtos Biológicos/metabolismo , Produtos Biológicos/farmacologia , Pironas/farmacologia , Urocordados/genética , Urocordados/metabolismo
5.
Chem Biol Drug Des ; 100(2): 290-303, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35555863

RESUMO

Kojic acid (KA) is a hydroxypyranone natural metabolite mainly known as tyrosinase inhibitor. Currently, this compound is used as a whitening agent in cosmetics and as an anti-browning agent in food industry. Given the easy-manipulation in different positions of the KA molecule, many investigations have been carried out to find new tyrosinase inhibitors derived from KA. Beside anti-tyrosinase activity, many KA-based compounds have been designed for targeting other enzymes including human neutrophil elastase, catechol-O-methyltransferase, matrix metalloproteinases, monoamine oxidase, human lactate dehydrogenase, endonucleases, D-amino acid oxidase, and receptors such as histamine H3 and apelin (APJ) receptors. This review could help biochemists and medicinal chemists in designing diverse KA-derived enzyme inhibitors.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos , Pironas , Catecol O-Metiltransferase , Desenho de Fármacos/métodos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Monofenol Mono-Oxigenase/antagonistas & inibidores , Pironas/química , Pironas/farmacologia
6.
J Hazard Mater ; 432: 128645, 2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35299107

RESUMO

Antibiotic tolerance has been a growing crisis that is seriously threatening global public health. However, little is known about the exogenous factors capable of triggering the development of antibiotic tolerance, particularly in vivo. Here we uncovered that an previously approved food additive termed sodium dehydroacetate (DHA-S) supplementation remarkably impaired the activity of bactericidal antibiotics against various bacterial pathogens. Mechanistic studies indicated that DHA-S induced glyoxylate shunt and reduced bacterial cellular respiration by inhibiting the enzymatic activity of α-ketoglutarate dehydrogenase (α-KGDH). Furthermore, DHA-S mitigated oxidative stress imposed by bactericidal antibiotics and enhanced the function of multidrug efflux pumps. These actions worked together to induce bacterial tolerance to antibiotic killing. Interestingly, the addition of five exogenous amino acids, particularly cysteine and proline, effectively reversed antibiotic tolerance elicited by DHA-S both in vitro and in mouse models of infection. Taken together, these findings advance our understanding of the potential risks of DHA-S in the treatment of bacterial infections, and shed new insights into the relationships between antibiotic tolerance and bacterial metabolism.


Assuntos
Antibacterianos , Pironas , Animais , Antibacterianos/toxicidade , Bactérias , Camundongos , Testes de Sensibilidade Microbiana , Pironas/farmacologia
7.
Microbiol Spectr ; 10(1): e0232021, 2022 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-35196789

RESUMO

Elasnin is a recently reported antibiofilm agent that is effective against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA). Remarkably, we observed that elasnin has a superior activity in eradicating daptomycin-resistant MRSA strain biofilm, with a lower minimum biofilm eradication concentration (MBEC) value of 0.625 µg/mL, compared to 2.5 µg/mL for the wild type. Confocal microscopy further confirmed the higher biofilm eradication on the daptomycin-resistant strain, displaying ∼53% decrease in cell density upon elasnin treatment, while the wild-type strain was only decreased by ∼15%. Quantitative proteomics revealed that the daptomycin-resistant strain has a lower expression of the membrane, cell wall, and extracellular proteins, and also proteins involved in the arginine biosynthesis, pathogenesis, and cell adhesion compared to the wild type, which may result in weaker biofilm development. This study highlights the potential clinical application of elasnin through its superior biofilm eradication activity against a daptomycin-resistant MRSA strain, and revealed the associated processes governing this superior activity through proteomics analysis. IMPORTANCE Due to the increased use of daptomycin for the treatment of MRSA infections, the emergence of daptomycin-resistant strains has become prevalent in recent years. In this study, we discovered that elasnin, a newly reported antibiofilm compound, has a superior activity in eradicating daptomycin-resistant MRSA strain biofilms compared to the wild type. Follow-up analysis revealed the reason behind this superior activity, which is the lower expression of key proteins that play a role in pathogenesis and cell adhesion in the daptomycin-resistant strain, leading to weaker biofilm development. This showcases the potential use of elasnin in clinical settings where daptomycin-resistant strains and biofilm formation are prevalent. Altogether, our study provides new insights into the mechanism of elasnin in MRSA biofilm cells and identified its superior biofilm eradicating activity in the daptomycin-resistant strain.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Daptomicina/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/fisiologia , Pironas/farmacologia , Infecções Estafilocócicas/microbiologia , Farmacorresistência Bacteriana , Humanos , Meticilina/farmacologia , Staphylococcus aureus Resistente à Meticilina/genética , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/tratamento farmacológico
8.
Fitoterapia ; 158: 105144, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35149120

RESUMO

Five new α-pyrones, cryptowratones A-E (1-5), and five known congeners (6-10), together with four other known compounds 11-14 were isolated from the twigs of Cryptocarya wrayi. The structures of the new compounds were elucidated on the basis of extensive spectroscopic data analysis and ECD calculations. All α-pyrones except 6 were evaluated for their stimulatory effects on glucose uptake in vitro with CHO-K1/GLUT4 cells. The positive control insulin displayed an approximate 42 ± 0.14% promotion on glucose uptake at 25 µM, compared with the CHO-K1/GLUT4 group. Compounds 1a/2a, 2, 3, and 10 showed a more significant stimulation of glucose uptake than insulin (25 µM) by 36 ± 0.08%, 27 ± 0.12%, 28 ± 0.12%, and 25 ± 0.12% at 1.5 µM, respectively. Immunofluorescence assays indicated the glucose uptake-stimulatory activity of α-pyrones might be correlated with increased GLUT4 translocation.


Assuntos
Cryptocarya , Cryptocarya/química , Glucose , Estrutura Molecular , Pironas/farmacologia
9.
Invest Ophthalmol Vis Sci ; 63(1): 4, 2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34982146

RESUMO

Purpose: Netarsudil, a Rho kinase inhibitor with norepinephrine transport inhibitory effect, lowers intraocular pressure, however, its effect on axon damage remains to be elucidated. The aim of the current study was to investigate the effect of netarsudil on TNF-induced axon loss and to examine whether it affects phosphorylated-AMP-activated kinase (p-AMPK) and autophagy in the optic nerve. Methods: Intravitreal administration of TNF or TNF with netarsudil was carried out on rats and quantification of axon number was determined. Electron microscopy determined autophagosome numbers. Localization of p-AMPK expression was examined by immunohistochemistry. The changes in p62, LC3-II, and p-AMPK levels were estimated in the optic nerve by immunoblot analysis. The effect of an AMPK activator A769662 or an AMPK inhibitor dorsomorphin on axon number was evaluated. Results: Morphometric analysis revealed apparent protection by netarsudil against TNF-induced axon degeneration. Netarsudil increased autophagosome numbers inside axons. Netarsudil treatment significantly upregulated optic nerve LC3-II levels in both the TNF-treated eyes and the control eyes. Increased p62 protein level induced by TNF was significantly ameliorated by netarsudil. The netarsudil administration alone lessened p62 levels. Netarsudil significantly upregulated the optic nerve p-AMPK levels. A769662 exhibited obvious axonal protection against TNF-induced damage. A769662 treatment upregulated LC3-II levels and the increment of p62 level induced by TNF was significantly ameliorated by A769662. Immunohistochemical analysis revealed that p-AMPK is present in axons. Netarsudil-mediated axonal protection was significantly suppressed by dorsomorphin administration. Conclusions: Netarsudil upregulated p-AMPK and autophagy. Netarsudil-mediated axonal protection may be associated with upregulated p-AMPK.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/fisiologia , Axônios/efeitos dos fármacos , Benzoatos/farmacologia , Degeneração Neural/prevenção & controle , Nervo Óptico/efeitos dos fármacos , Fator de Necrose Tumoral alfa/toxicidade , beta-Alanina/análogos & derivados , Quinases Associadas a rho/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Animais , Axônios/enzimologia , Axônios/patologia , Compostos de Bifenilo/farmacologia , Inibidores Enzimáticos/farmacologia , Imuno-Histoquímica , Injeções Intravítreas , Masculino , Microscopia Eletrônica , Proteínas Associadas aos Microtúbulos/metabolismo , Degeneração Neural/enzimologia , Nervo Óptico/ultraestrutura , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Pironas/farmacologia , Ratos , Ratos Wistar , Proteína Sequestossoma-1/metabolismo , Tiofenos/farmacologia , beta-Alanina/farmacologia
10.
Microb Cell Fact ; 21(1): 1, 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34983506

RESUMO

BACKGROUND: With the steady increase of antibiotic resistance, several strategies have been proposed in the scientific community to overcome the crisis. One of many successful strategies is the re-evaluation of known compounds, which have been early discarded out of the pipeline, with state-of-the-art know-how. Xanthoepocin, a polyketide widespread among the genus Penicillium with an interesting bioactivity spectrum against gram-positive bacteria, is such a discarded antibiotic. The purpose of this work was to (i) isolate larger quantities of this metabolite and chemically re-evaluate it with modern technology, (ii) to explore which factors lead to xanthoepocin biosynthesis in P. ochrochloron, and (iii) to test if it is beside its known activity against methicillin-resistant Staphylococcus aureus (MRSA), also active against linezolid and vancomycin-resistant Enterococcus faecium (LVRE)-a very problematic resistant bacterium which is currently on the rise. RESULTS: In this work, we developed several new protocols to isolate, extract, and quantify xanthoepocin out of bioreactor batch and petri dish-grown mycelium of P. ochrochloron. The (photo)chemical re-evaluation with state-of-the-art techniques revealed that xanthoepocin is a photolabile molecule, which produces singlet oxygen under blue light irradiation. The intracellular xanthoepocin content, which was highest under ammonium-limited conditions, varied considerably with the applied irradiation conditions in petri dish and bioreactor batch cultures. Using light-protecting measures, we achieved MIC values against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), which were up to 5 times lower than previously published. In addition, xanthoepocin was highly active against a clinical isolate of linezolid and vancomycin-resistant Enterococcus faecium (LVRE). CONCLUSIONS: This interdisciplinary work underlines that the re-evaluation of known compounds with state-of-the-art techniques is an important strategy in the combat against multiresistant bacteria and that light is a crucial factor on many levels that needs to receive more attention. With appropriate light protecting measures in the susceptibility tests, xanthoepocin proved to be a powerful antibiotic against MRSA and LVRE. Exploring the light response of other polyketides may be pivotal for re-introducing previously discarded metabolites into the antibiotic pipeline and to identify photosensitizers which might be used for (antimicrobial) photodynamic therapies.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla , Compostos de Epóxi/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Luz , Penicillium/química , Pironas/farmacologia , Difusão Dinâmica da Luz , Testes de Sensibilidade Microbiana , Fotólise
11.
J Nat Prod ; 85(2): 384-390, 2022 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-35057611

RESUMO

Diterpenoid pyrones are a type of mainly fungal meroterpenoid metabolite consisting of a diterpene connected to a pyrone, some of which show potent bioactivity. Through genome mining and heterologous expression, nine new diterpenoid pyrones, shearones A-I (1-9), were discovered from the fungus Eupenicillium shearii IFM 42152, and their biosynthetic enzyme activities were revealed. Some of these heterologously biosynthesized diterpenoid pyrones exhibited moderate antiaggregative ability against amyloid ß42 in vitro.


Assuntos
Diterpenos , Pironas , Diterpenos/metabolismo , Diterpenos/farmacologia , Penicillium , Pironas/farmacologia , Biologia Sintética
12.
Biomed Pharmacother ; 147: 112663, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35093759

RESUMO

Memory-enhancing agents have long been required for various reasons such as for obtaining a good score in a test in the young and for retaining memory in the aged. Although many studies have found that several natural products may be good candidates for memory enhancement, there is still a need for better agents. The present study investigated whether rubrofusarin, an active ingredient in Cassiae semen, enhances learning and memory in normal mice. Passive avoidance and Morris water maze tests were performed to determine the memory-enhancing ability of rubrofusarin. To investigate synaptic function, hippocampal long-term potentiation (LTP) was measured. Western blotting was performed to determine protein levels. To investigate neurite outgrowth, DCX immunohistochemistry and cell culture were utilised. Rubrofusarin (1, 3, 10, 30 mg/kg) enhanced memory in passive avoidance and Morris water maze tests. Moreover, rubrofusarin ameliorated scopolamine-induced memory impairment. In the rubrofusarin-treated group, high-frequency stimulation induced higher LTP in the hippocampal Schaffer-collateral pathway compared to the control group. The rubrofusarin-treated group showed a higher number of DCX-positive immature neurons with an increase in the length of dendrites compared to the control group in the hippocampal dentate gyrus region. In vitro experiments showed that rubrofusarin facilitated neurite outgrowth in neuro2a cells through extracellular signal-regulated kinase (ERK). Finally, we found that extracellular signal-regulated kinase (ERK) is required for rubrofusarin-induced enhancement of neurite outgrowth, learning and memory. These results demonstrate that rubrofusarin enhances learning and memory and neurite outgrowth, and these might need activation of ERK pathway.


Assuntos
Cognição/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , Crescimento Neuronal/efeitos dos fármacos , Pironas/farmacologia , Animais , Técnicas de Cultura de Células , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos , Pironas/administração & dosagem
13.
Mar Drugs ; 20(1)2022 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-35049926

RESUMO

Six new α-pyrone meroterpenoid chevalones H-M (1-6), together with six known compounds (7-12), were isolated from the gorgonian coral-derived fungus Aspergillus hiratsukae SCSIO 7S2001 collected from Mischief Reef in the South China Sea. Their structures, including absolute configurations, were elucidated on the basis of spectroscopic analysis and X-ray diffraction data. Compounds 1-5 and 7 showed different degrees of antibacterial activity with MIC values of 6.25-100 µg/mL. Compound 8 exhibited potent cytotoxicity against SF-268, MCF-7, and A549 cell lines with IC50 values of 12.75, 9.29, and 20.11 µM, respectively.


Assuntos
Antozoários , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Aspergillus , Pironas/farmacologia , Animais , Antibacterianos/química , Antineoplásicos/química , Organismos Aquáticos , Linhagem Celular Tumoral , China , Humanos , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Pironas/química
14.
J Nat Med ; 76(2): 462-467, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34981405

RESUMO

Diaportholides A (1) and B (2), two polyketides with ɑ-pyrone moieties, were isolated from the cultures of an endophytic Diaporthe sp. ECN371 isolated from Orixa japonica, together with four known polyketides, phomopsolide B (3), phomopsolidones A (4) and B (5), and 5-[(1R)-1-hydroxyethyl]-γ-oxo-2-furanbutanoic acid (6). The structures of 1 and 2 were determined by extensive analysis of NMR and MS spectroscopic data. Furthermore, the structure of 2 was confirmed by analyzing the single-crystal X-ray diffraction data. The luciferase reporter gene assay revealed that among all isolated compounds (1-6), 3, a known ɑ-pyrone derivative, exhibited agonistic activity against the peroxisome proliferator-activated receptor ɑ, which is an important regulator of lipid metabolism in humans.


Assuntos
Policetídeos , Pironas , Cristalografia por Raios X , Humanos , Estrutura Molecular , Policetídeos/farmacologia , Pironas/farmacologia
15.
Can J Physiol Pharmacol ; 100(1): 43-52, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34425056

RESUMO

A gamma-pyrone derivative, comenic acid, activates the opioid-like receptor-mediated signaling pathway that modulates the NaV1.8 channels in the primary sensory neuron membrane. These channels are responsible for the generation of the nociceptive signal; therefore, gamma-pyrones have great therapeutic potential as analgesics, and this effect deserves a deeper understanding. The novelty of our approach to the design of a medicinal substance is based on a combination of the data obtained from living neurons using very sensitive physiological methods and the results of quantum chemical calculations. This approach allows the correlation of the molecular structure of gamma-pyrones with their ability to evoke a physiological response of the neuron. Comenic acid can bind to two calcium cations. One of them is chelated by the carbonyl and hydroxyl functional groups, while the other forms a salt bond with the carboxylate anion. Calcium-bound gamma-pyrones have fundamentally different electrostatic properties from free gamma-pyrone molecules. These two calcium ions are key elements involved in ligand-receptor binding. It is very likely that ion-ionic interactions between these cations and anionic functional groups of the opioid-like receptor activate the latter. The calculated intercationic distance of 9.5 Å is a structural criterion for effective ligand-receptor binding of calcium-bound gamma-pyrones.


Assuntos
Analgésicos , Desenho de Fármacos/métodos , Desenho de Fármacos/tendências , Pironas , Animais , Cálcio , Ácidos Carboxílicos , Embrião de Galinha , Imunofluorescência , Humanos , Íons , Canal de Sódio Disparado por Voltagem NAV1.8 , Pironas/química , Pironas/farmacologia , Receptores Opioides
16.
Nat Prod Res ; 36(15): 3872-3878, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33648402

RESUMO

Two new pyrone derivatives, 2-(12S-hydroxypropyl)-3-hydroxy-methyl-6-hydroxy-7-methoxychromone (1), and (±)-pyrenocine S (5), together with five known compounds xanthoradone A (2), (+)-3,3',7,7',8,8'-hexahydroxy-5,5'-dimethyl-bianthra-quinone (3), butyrolactone-I (4), pyrenocine A (6), and (±)-pyrenocine E (7) were obtained from the mangrove endophytic fungus Aspergillus sydowii #2B. Their structures were elucidated on the basis of spectroscopic methods, single-crystal X-ray diffraction analysis and comparison data with of literatures. Compounds 2, 3, 4, 5, 6 and 7 showed cytotoxicities against prostate cancer VCaP cells with IC50 values of 4.19 ± 1.02, 33.36 ± 1.42, 1.92 ± 0.82, 20.06 ± 2.01, 7.92 ± 0.86, and 10.13 ± 0.88 µM respectively, while compound 1 showed no cytotoxic activity. Compounds 1, 3, 6, and 7 exhibited weak inhibition effects against the production of nitric oxide (NO) in lipopolysaccharide (LPS)-induced RAW 246.7 cells with IC50 values of 40.15, 28.69, 25.25 and 43.08 µM respectively.


Assuntos
Aspergillus , Pironas , Aspergillus/química , Fungos , Estrutura Molecular , Pironas/química , Pironas/farmacologia
17.
Nat Prod Res ; 36(11): 2707-2712, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33949256

RESUMO

Chemical investigation of Paxillus involutus (Batsch) Fr. led to the isolation of a pair of new enantiomers (E)-5-(4-methoxy-2-oxo-2H-pyran-6-yl)pent-4-en-1-yl 2-hydroxypropanoate (1a/1b) along with 14 known compounds (2-15) for the first time from this mushroom. The structures of new compounds were elucidated based on extensive spectroscopic data analysis of MS, 1D and 2D NMR, and their absolute configurations were confirmed by comparison of the experimental and calculated ECD data. Compounds 1a and 1b exhibited radical scavenging activities with IC50 values ranging from 10.39 ± 2.26 to 20.43 ± 3.74 µg/mL. Compounds 1a and 1b also showed moderate anti-tyrosinase activity with IC50 value of 25.66 ± 2.84 and 26.82 ± 3.19 µg/mL.


Assuntos
Agaricales , Basidiomycota , Agaricales/química , Estrutura Molecular , Monofenol Mono-Oxigenase , Pironas/farmacologia
18.
Bioorg Med Chem ; 54: 116579, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34954618

RESUMO

Four series of molecular hybrids (37 final products) of neo-tanshinlactone, a natural product extracted from Salvia miltiorrhiza Bunge, and known PD-1/PD-L1 interaction inhibitors were prepared as possible chemotherapeutic agents against triple negative breast cancer. Screening using a homogenous time-resolved fluorescence method resulted in three lead compounds (MZ52 IC50 74 ± 4 nM; MZ58 IC50 134 ± 17 nM; MZ61 IC50 225 ± 19 nM). With less T cell cytotoxicity and effects in activating CD8+ T cells in a T cell proliferation assay and a functionality experiment, MZ58 was selected as the best candidate for animal experiments. MZ58 exhibited antitumor effects in a subcutaneous transplantation tumor model as well as effects in reducing T cell exhaustion. In conclusion, after in vivo and in vitro experiments, we successfully acquired an effective candidate (MZ58) showing antitumor effects with low cytotoxicity toward T cells as well as the ability to activate CD8+ T cells and reduce T cell exhaustion.


Assuntos
Antineoplásicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Desenho de Fármacos , Furanos/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Pironas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/síntese química , Furanos/química , Humanos , Inibidores de Checkpoint Imunológico/síntese química , Inibidores de Checkpoint Imunológico/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Receptor de Morte Celular Programada 1/metabolismo , Pironas/síntese química , Pironas/química , Relação Estrutura-Atividade
19.
Microbiol Res ; 254: 126911, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34763140

RESUMO

As a major secondary metabolite derived from a dominant marine filamentous fungus A7, kojic acid might confer the strain a competitive advantage in natural colonization. The bioactivities of kojic acid against bacterial growth and biofilm formation were investigated against Acinetobacter baumannii (A. baumannii) ATCC 19606. Then, transcriptomics and metabolomics were integrated to characterize the underlying mechanisms. It turned out that kojic acid exhibited a significantly suppressive impact against biofilm but a weak bacteriostatic activity. Meanwhile, a variety of transcriptional and metabolomic profiles were altered within biofilm formation as a result of kojic acid exposure. The alterations highlighted the mechanisms underlying biofilm formation, comprising of quorum sensing, fimbria assembly, bacterial virulence and metabolic plasticity, which could somewhat be hampered by kojic acid. The present study comprehensively elucidated multifactorial schemes for kojic acid combating biofilm formation of A. baumannii, which might provide mechanistic insights into the development of therapeutic strategies against this notorious pathogen. Meanwhile, our observations might shed new light on the ecological roles of kojic acid, e.g., serving as chemical deterrents for host adaptation to marine niches, which, however, awaits further validation.


Assuntos
Acinetobacter baumannii , Biofilmes , Metaboloma , Pironas , Transcriptoma , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/genética , Biofilmes/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Metabolômica , Pironas/farmacologia , Transcriptoma/efeitos dos fármacos
20.
J Appl Biomed ; 19(3): 159-169, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34907759

RESUMO

AMP-activated protein kinase (AMPK) signaling shows an important role in energy metabolism and has recently been involved in osteogenic and adipogenic differentiation. In this study we aimed to investigate the role of AMPK activator, A-769662, in regulating the differentiation of mesenchymal stem cells derived from bone marrow (BMSCs) into osteoblastic and adipocytic cell lineage. The effect of A-769662 on osteogenesis was assessed by quantitative alkaline phosphatase (ALP) activity, matrix mineralization stained with Alizarin red, and gene expression analysis by quantitative polymerase chain reaction (qPCR). Adipogenesis was determined by Oil Red O staining for fat droplets and qPCR analysis of adipogenic markers. A-769662 activated the phosphorylation of AMPKα1 during the osteogenesis of mBMSCs as revealed by western blot analysis. A-769662 promoted the early stage of the commitment of mouse (m) BMSCs differentiation into osteoblasts, while inhibiting their differentiation into adipocytes in a dose-dependent manner. The effects of A-769662 on stimulating osteogenesis and inhibiting adipogenesis of mBMSCs were significantly eliminated in the presence of either AMPKα1 siRNA or Compound C, an inhibitor of AMPK pathway. In conclusion, we identified A-769662 as a new compound that promotes the commitment of BMSCs into osteoblasts versus adipocytes via AMPK-dependent mechanism. Thus our data show A-769662 as a potential osteo-anabolic drug for treatment of osteoporosis.


Assuntos
Proteínas Quinases Ativadas por AMP , Compostos de Bifenilo , Células-Tronco Mesenquimais , Pironas , Tiofenos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Compostos de Bifenilo/farmacologia , Medula Óssea , Diferenciação Celular , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Osteoblastos , Pironas/farmacologia , Tiofenos/farmacologia
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