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1.
Phytomedicine ; 130: 155789, 2024 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-38824826

RESUMEN

BACKGROUND: Bacteria within biofilms are thousand times more resistant to antibiotics. Neuraminidase is a crucial enzyme for bacterial adhesion and biofilm formation, it hydrolyzes glycosidic residue of glycoproteins, glycolipids, and oligosaccharides. Coreopsis lanceolata L. flowers may have a significant potential of bacterial neuraminidase (BNA) inhibition because of high natural abundance of chalcones. PURPOSE: The investigation of bacterial biofilm inhibitors has emerged as a novel therapeutic strategy against antibiotic resistance. Therefore, individual chalcones were isolated from C. lanceolata and their capacity to inhibit BNA and formation of Escherichia coli biofilm were evaluated. METHODS: Different chromatographic techniques were used to isolate the compounds (1-12). Enzyme inhibition and detailed kinetic behavior of compounds was determined by estimation of kinetic parameters (Michaelis-Menten constants (Km), maximum velocity (Vmax), dissociation constant for binding with the free enzyme (KI) and enzyme-substate complex (KIS)). Binding affinities (KSV) and binding modes of inhibitors were elucidated by fluorescence quenching and molecular docking, respectively. The natural abundance of chalcones was established through UPLC-Q-TOF/MS. The most potent inhibitor (1) was tested for its ability to inhibit the formation of E. coli biofilm, which was examined by crystal violet assay, scanning electron microscope (SEM) and confocal laser scanning microscope (CLSM). RESULTS: A series of eight chalcones (1-8) and four chalcone glucosides (9-12), inhibited BNA in a dose-dependent manner with IC50 of 8.3 ∼ 77.0 µM. The most potent chalcones were butein (1, IC50 = 8.3 µM) and its glucoside 9 (IC50 = 13.8 µM). The aglycones (1-8) showed non-competitive inhibition, while chalcone glucosides (9-12) displayed a mixed type I (KI < KIS). Inhibitory behaviors were doubly confirmed by KSV and matched with tendency of IC50. The functional group responsible for BNA inhibition were disclosed as 4'-hydroxyl group on B-ring by structure activity relationship (SAR) and molecular docking experiments. Butein (1) suppressed E. coli biofilm formation by > 50 % at 100 µM according to crystal violet assay, which was confirmed by SEM and CLSM imaging. CONCLUSION: The results showed that chalcones (1-8) and chalcone glucosides (9-12), metabolites isolated from the flowers of C. lanceolata, had BNA inhibitory and antibiofilm formation effect on E. coli.


Asunto(s)
Antibacterianos , Biopelículas , Chalconas , Coreopsis , Escherichia coli , Flores , Neuraminidasa , Antibacterianos/farmacología , Antibacterianos/química , Biopelículas/efectos de los fármacos , Chalconas/farmacología , Chalconas/química , Coreopsis/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Escherichia coli/efectos de los fármacos , Flores/química , Cinética , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Neuraminidasa/antagonistas & inhibidores , Extractos Vegetales/farmacología , Extractos Vegetales/química
2.
ACS Omega ; 9(8): 9053-9062, 2024 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-38434867

RESUMEN

Protein tyrosine phosphatase 1B (PTP1B) is one of the target enzymes whose disruption leads to obesity and diabetes. A series of PTP1B inhibitors were isolated from the leaves of Artocarpus elasticus, used in traditional medicines for diabetes. The isolated inhibitors (1-13), including two new compounds (1 and 2), consisted of dihydroflavonols and flavones. The structural requirements for the PTP1B inhibitory mode and potency were revealed in both skeletons. The two highest PTP1B inhibitory properties were dihydroflavonol 1 and flavone 6 analogs with IC50 values of 0.17 and 0.79 µM, respectively. The stereochemistry also affected inhibitory potencies: trans isomer 1 (IC50= 0.17 µM) vs cis isomer 2 (IC50= 2.24 µM). Surprisingly, the dihydroflavonol and flavone glycosides (11 and 13) displayed potent inhibition with IC50s of 2.39 and 0.22 µM, respectively. Furthermore, competitive inhibitor 1 was applied to time-dependence experiments as a simple slow-binding inhibitor with parameters of Kiapp = 0.064103 µM, k3 = 0.2262 µM-1 min-1, and k4 = 0.0145 min-1. The binding affinities by using the fluorescence quenching experiment were highly correlated with inhibitory potencies: 1 (IC50= 0.17 µM, KSV = 0.4375 × 105 L·mol-1) vs 3 (IC50= 17.79 µM, KSV = 0.0006 × 105 L·mol-1). The specific binding interactions were estimated at active and allosteric sites according to the inhibitory mode by molecular docking.

3.
Lab Anim Res ; 40(1): 4, 2024 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-38355576

RESUMEN

Phytoestrogens, such as isoflavones, are known for their capacity to simulate various physiological impacts of estrogen in the human body. Our research evaluated the effects of isoflavone-enriched soybean leaves (IESL) on collagen fiber loss prompted by ovariectomy in Sprague Dawley (SD) rats, thereby simulating menopausal changes in women. IESL, bolstered with an increased concentration of isoflavones through a metabolite farming process, contained a significantly higher amount of isoflavones than regular soybean leaves. Our results indicate that the administration of IESL can counteract the decrease in relative optical density and dermal thickness of collagen fibers caused by ovariectomy in SD rats, with more pronounced effects observed at higher isoflavone dosages. These outcomes suggest that soybean leaves rich in isoflavones may hold potential benefits in combating collagen degradation and skin aging symptoms related to menopause. Further research is needed to fully understand the exact molecular pathways at play and the potential clinical relevance of these findings.

4.
Plant Signal Behav ; 18(1): 2287883, 2023 Dec 31.
Artículo en Inglés | MEDLINE | ID: mdl-38019725

RESUMEN

Soybean, a vital protein-rich crop, offers bioactivity that can mitigate various chronic human diseases. Nonetheless, soybean breeding poses a challenge due to the negative correlation between enhanced protein levels and overall productivity. Our previous studies demonstrated that applying gaseous phytohormone, ethylene, to soybean leaves significantly boosts the accumulation of free amino acids, particularly asparagine (Asn). Current studies also revealed that ethylene application to soybeans significantly enhanced both essential and non-essential amino acid contents in leaves and stems. Asn plays a crucial role in ammonia detoxification and reducing fatigue. However, the molecular evidence supporting this phenomenon remains elusive. This study explores the molecular mechanisms behind enhanced Asn accumulation in ethylene-treated soybean leaves. Transcriptional analysis revealed that ethylene treatments to soybean leaves enhance the transcriptional levels of key genes involved in Asn biosynthesis, such as aspartate aminotransferase (AspAT) and Asn synthetase (ASN), which aligns with our previous observations of elevated Asn levels. These findings shed light on the role of ethylene in upregulating Asn biosynthetic genes, subsequently enhancing Asn concentrations. This molecular insight into amino acid metabolism regulation provides valuable knowledge for the metabolic farming of crops, especially in elevating nutraceutical ingredients with non-genetic modification (GM) approach for improved protein content.


Asunto(s)
Asparagina , Glycine max , Aminoácidos/metabolismo , Asparagina/genética , Asparagina/análisis , Asparagina/metabolismo , Etilenos/metabolismo , Semillas/metabolismo , Glycine max/genética , Glycine max/metabolismo
5.
ACS Omega ; 8(35): 31870-31879, 2023 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-37692245

RESUMEN

A series of rotenoids including a new one from the seeds of Amorpha fruticosa were found to have significant potential as tyrosinase inhibitors. All of the isolated rotenoids (1-6) displayed inhibitory activity against tyrosinase, both as a monophenolase for the oxidation of l-tyrosine and as a diphenolase for the oxidation of l-DOPA. The three most active compounds (1, 5, and 6) showed significant monophenolase inhibition with IC50 values of 2.1, 1.7, and 1.2 µM, respectively. They also inhibited diphenolase function with IC50 values in the range of 9.5-21.5 µM. The inhibition kinetics established all compounds to be competitive inhibitors of both oxidation processes. All rotenoids formed the Emet·I complex effectively around their IC50 values with long lag times. Tyrosinase inhibition of the new rotenoid 6 was additionally demonstrated using high-performance liquid chromatography (HPLC) analysis with N-acetyl-l-tyrosine. Molecular docking disclosed that the sugar moiety of 5 interacted with the bottom of the catalytic gorge.

6.
Biomed Pharmacother ; 165: 115278, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37536031

RESUMEN

Exposure to reactive oxygen species (ROS) leads to the oxidation of low-density lipoproteins (LDL), converting them into oxidized ones (oxLDL), which are involved in the pathogenesis of Alzheimer's disease, suggesting a potential link between lipid dysregulation and neurodegenerative processes. Phenolic metabolites derived from Artocarpus elasticus root bark were found to possess significant antioxidant properties at three different radical scavenging assays, including 2,2-diphenyl-1-picrylhydrazyl (DPPH), oxygen radical absorbance capacity (ORAC), and thiobarbituric acid reactive substances (TBARS). Among them, furanodihydrobenzoxanthones (1-3) demonstrated notable protection against Cu2+ induced LDL oxidation, with IC50 values ranging from 0.9 to 2.9 µM in measurement of the malondialdehyde (MDA) production at TBARS and prolonged lag times (>180 min) in the generation of conjugated diene (CD). At a concentration of 10 µM, all three compounds (1-3) effectively protected against LDL oxidation as determined by relative electrophoretic mobility (REM). The most potent compound 1 defended human neuroblastoma SH-SY5Y cells from oxLDL-mediated dysfunction, including oxLDL-induced cytotoxicity, inhibited reactive oxygen species (ROS) formation, and enhancing mitochondrial membrane potential (ΔΨm). Individual components annotation in the ethylacetate extract was performed using LC-ESI-QTOF/MS, which serves as a chemotaxonomic marker for A. elasticus root barks.


Asunto(s)
Antioxidantes , Neuroblastoma , Humanos , Antioxidantes/farmacología , Antioxidantes/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Lipoproteínas LDL/farmacología , Oxidación-Reducción
7.
Front Chem ; 11: 1245071, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37621851

RESUMEN

Introduction: The root of Cratoxylum cochinchinense has been widely used as Chinese folk medicine to cure fevers, burns, and abdominal complications because it contains various bioactive metabolites such as xanthones, triterpenes, and flavonoids. In this study, we estimated bacterial neuraminidase inhibition with a series of xanthones from C. cochinchinense. BNA has connected to various biological functions such as pathogenic bacteria infection inflammatory process after infection and biofilm formation. Methods: The identification of xanthones (1-6) bearing geranyl and prenyl groups was established by spectroscopic data using UV, IR, NMR, and HREIMS. BNA inhibitory modes of isolated xanthones were investigated by Double-reciprocal plots. Moreover, the competitive inhibitor was evaluated the additional kinetic modes determined by kinetic parameters (k 3, k 4, and K i app). The molecular docking (MD) and molecular dynamics simulations (MDS) studies also provided the critical information regarding the role of the geranyl and prenyl groups against BNA inhibition. Results: A series of xanthones (1-6) appended prenyl and geranyl groups on the A-ring were isolated, and compounds 1-3 were shown to be new xanthones. The analogues within this series were highly inhibited with excellent affinity against bacterial neuraminidase (BNA). A subtle change in the prenyl or geranyl motif affected the inhibitory potency and behavior significantly. For example, the inhibitory potency and binding affinity resulting from the geranyl group on C4: xanthone 1 (IC50 = 0.38 µM, KA = 2.4434 × 105 L·mol-1) were 100-fold different from those of xanthone 3 (IC50 = 35.8 µM, KA = 0.0002 × 105 L·mol-1). The most potent compound 1 was identified as a competitive inhibitor which interacted with BNA under reversible slow-binding inhibition: K i app = 0.1440 µM, k 3 = 0.1410 µM-1s-1, and k 4 = 0.0203 min-1. The inhibitory potencies (IC50) were doubly confirmed by the binding affinities (KA). Discussion: This study suggests the potential of xanthones derived from C. cochinchinense as promising candidates for developing novel BNA inhibitors. Further research and exploration of these xanthones may contribute to the development of effective treatments for bacterial infections and inflammatory processes associated with BNA activity.

8.
Molecules ; 28(14)2023 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-37513238

RESUMEN

This study aimed to isolate bacterial neuraminidase (BNA) inhibitory O-methylated quercetin derivatives from the aerial parts of S. pubescens. All the isolated compounds were identified as O-methylated quercetin (1-4), which were exhibited to be noncompetitive inhibitors against BNA, with IC50 ranging from 14.0 to 84.1 µM. The responsible compounds (1-4) showed a significant correlation between BNA inhibitory effects and the number of O-methyl groups on quercetin; mono (1, IC50 = 14.0 µM) > di (2 and 3, IC50 = 24.3 and 25.8 µM) > tri (4, IC50 = 84.1 µM). In addition, the binding affinities between BNA and inhibitors (1-4) were also examined by fluorescence quenching effect with the related constants (KSV, KA, and n). The most active inhibitor 1 possessed a KSV with 0.0252 × 105 L mol-1. Furthermore, the relative distribution of BNA inhibitory O-methylated quercetins (1-4) in S. pubescens extract was evaluated using LC-Q-TOF/MS analysis.


Asunto(s)
Asteraceae , Quercetina , Quercetina/farmacología , Neuraminidasa , Sigesbeckia , Asteraceae/química , Componentes Aéreos de las Plantas , Extractos Vegetales/farmacología
9.
J Agric Food Chem ; 71(27): 10393-10402, 2023 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-37358831

RESUMEN

The low levels of bioactive metabolites in target plants present a bottleneck for the functional food industry. The major disadvantage of soy leaves is their low phytoestrogen content despite the fact that these leaves are an enriched source of flavonols. Our study demonstrated that simple foliar spraying with 1-aminocyclopropane-1-carboxylic acid (ACC) significantly enhanced the phytoestrogen contents of the whole soy plant, including its leaves (27-fold), stalks (3-fold), and roots (4-fold). In particular, ACC continued to accelerate the biosynthesis pathway of isoflavones in the leaves for up to 3 days after treatment, from 580 to 15,439 µg/g. The detailed changes in the levels of this metabolite in soy leaves are disclosed by quantitative and metabolomic analyses based on HPLC and UPLC-ESI-TOF/MS. The PLS-DA score plot, S-plot, and heatmap provide comprehensive evidence to clearly distinguish the effect of ACC treatment. ACC was also proved to activate a series of structural genes (CHS, CHR, CHI, IFS, HID, IF7GT, and IF7MaT) along the isoflavone biosynthesis pathway time-dependently. In particular, ACC oxidase genes were turned on 12 h after ACC treatment, which was rationalized to start activating the synthetic pathway of isoflavones.


Asunto(s)
Isoflavonas , Isoflavonas/metabolismo , Glycine max/química , Fitoestrógenos , Vías Biosintéticas , Aceleración
10.
Nutrients ; 14(22)2022 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-36432439

RESUMEN

(1) Background: The estrogen decline during perimenopause can induce various disorders, including cognitive impairment. Phytoestrogens, such as isoflavones, lignans, and coumestans, have been tried as a popular alternative to avoid the side effects of conventional hormone replacement therapy, but their exact mechanisms and risk are not fully elucidated. In this study, we investigated the effects of isoflavone-enriched soybean leaves (IESLs) on the cognitive impairment induced by ovariectomy in female mice. (2) Methods: Ovariectomy was performed at 9 weeks of age to mimic menopausal women, and the behavior tests for cognition were conducted 15 weeks after the first administration. IESLs were administered for 18 weeks. (3) Results: The present study showed the effects of IESLs on the cognitive function in the OVX (ovariectomized) mice. Ovariectomy markedly increased the body weight and fat accumulation in the liver and perirenal fat, but IESL treatment significantly inhibited them. In the behavioral tests, ovariectomy impaired cognitive functions, but administration of IESLs restored it. In addition, in the OVX mice, administration of IESLs restored decreased estrogen receptor (ER) ß and PI3K/Akt expression in the hippocampus. (4) Conclusions: The positive effects of IESLs on cognitive functions may be closely related to the ER-mediated PI3/Akt signaling pathway in the hippocampus.


Asunto(s)
Disfunción Cognitiva , Glycine max , Isoflavonas , Ovariectomía , Fitoterapia , Animales , Femenino , Humanos , Ratones , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Estrógenos , Hipocampo/efectos de los fármacos , Isoflavonas/farmacología , Isoflavonas/uso terapéutico , Ratones Endogámicos C57BL , Ovariectomía/efectos adversos , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Hojas de la Planta
11.
Front Plant Sci ; 13: 1000705, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36226298

RESUMEN

Abundance of metabolites in plant is a critical factor toward being functional food stuff. Salicylic acid (SA) treatment led significant changes in levels of the secondary metabolites in soybean roots. Notably, the exposure of 3 mM of SA aqueous solution to soybean plants for 24 h resulted in distinctive increases in the levels of coumestrol (16-fold, 0.3-4.8 mg/g DW) and daidzein (7-fold, 1.2-8.9 mg/g DW) in roots part. These changes were systematically investigated by LC-ESI-TOF/MS analysis to afford a clear difference of PLS-DA score, heatmap, and box plots. Quantitative analysis showed that SA treatment played to stimulate biosynthesis of coumestrol as well as hydrolysis of its glycosides (coumestrin and malonylcoumestrin). The highly improved anti-LDL oxidation effect was observed in the SA treated soybean roots in the three different assay systems. It might be rationalized by the increased levels of coumestrol and daidzein.

12.
Curr Issues Mol Biol ; 44(7): 2856-2867, 2022 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-35877420

RESUMEN

In this study, we investigated the depigmentation effect of Amorpha fruticosa L. root extract (RE), an herbal medicine. A. fruticosa RE significantly induced depigmentation in α-MSH-treated B16F10 cells at noncytotoxic concentrations. Further, the RE decreased the protein levels of the melanosomal proteins Tyr and Pmel without decreasing their transcript levels. We found that MG132, a proteasome complex inhibitor, was unable to rescue the protein levels, but PepA/E-64D (a lysosomal enzyme inhibitor), 3-MA (a representative autophagy inhibitor), and ATG5 knockdown effectively rescued the protein levels and inhibited the depigmentation effect following RE treatment. Among rotenoids, amorphigenin composed in the RE was identified as a functional chemical that could induce depigmentation; whereas rapamycin, an mTOR inhibitor and a nonselective autophagy inducer, could not induce depigmentation, and amorphigenin effectively induced depigmentation through the degradation of melanosomal proteins. Amorphigenin activated AMPK without affecting mTOR, and knockdown of AMPK offset the whitening effect through degradation of melanosome proteins by amorphigenin. Results from this study suggested that amorphigenin can induce degradation of the melanosome through an AMPK-dependent autophagy process, and has the potential to be used as a depigmentation agent for the treatment of hyperpigmentation.

13.
Bioorg Chem ; 127: 105978, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35752099

RESUMEN

Artocarpus elasticus is a popular fruit tree in the tropical regions. Primary screenings of methanol extracts of the root bark confirmed its potent inhibition of bacterial neuraminidase (BNA), which plays an essential role in the pathogenesis of many microbial diseases. Assessments of the responsible phytochemicals were conducted by isolating eight compounds (1-8) and two of them (6 and 8) were identified as new compounds. Among the isolates, the dihydrobenzoxanthones attained the highest BNA inhibition with IC50 values of 0.5 âˆ¼ 3.9 µM. Further investigation of the inhibitory mechanism by Lineweaver-Burk plots revealed the phytochemicals to function as reversible noncompetitive inhibitors. Fluorescence quenching showed their binding affinities were highly correlated with their inhibitory potential dose-dependently. Molecular docking experiments suggested the dihydrobenzoxanthones (4 and 6) as noncompetitive inhibitors of BNA with unique interaction with Tyr435 of BNA in comparison with the mother flavonoid (7).


Asunto(s)
Artocarpus , Artocarpus/química , Bacterias , Flavonoides/química , Simulación del Acoplamiento Molecular , Neuraminidasa , Fitoquímicos , Extractos Vegetales/química
14.
Food Funct ; 13(13): 6923-6933, 2022 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-35695875

RESUMEN

Ethanol extract of soybean (Glycine max (L.) Merr.) showed good inhibitory activity against bacterial neuraminidase (BNA), which plays a pivotal role in the pathogenesis of a number of microbial diseases. The saponin portion fractionated through preparative HPLC (IC50 = 2.25 µg mL-1) was found to be responsible for the observed BNA inhibition. Estimation of the inhibitory effects by individual compounds showed that the soyasaponins of group B (Ba, Bb, Bb', Bc, and Bd) exhibited extremely high inhibitions (IC50 = 0.25-0.48 µM), whereas group A (Aa, Ab, and Ac) was almost inactive. Kinetic studies determined that group B soyasaponins were noncompetitive inhibitors. Furthermore, molecular docking experiments confirmed that soyasaponin Ba (group B) could undergo binding interactions with various residues in the binding pocket. In contrast, soyasaponin Aa (group A) failed to enter the binding pocket due to its extra scaffold structure of oligosaccharides bonded to the 22-hydroxyl position. The metabolites in the soybean extract were fully characterized using UPLC-ESI-TOF/MS.


Asunto(s)
Fabaceae , Saponinas , Cromatografía Líquida de Alta Presión , Cinética , Simulación del Acoplamiento Molecular , Neuraminidasa , Fitoquímicos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Saponinas/química , Saponinas/farmacología , Glycine max/química
15.
Front Pharmacol ; 13: 890649, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35645800

RESUMEN

Bacterial neuraminidase (BNA) plays a pivotal role in the pathogenesis of several microbial diseases including biofilm formation. The aim of this study is to reveal the neuraminidase inhibitory potential of metabolites from Helminthostachys zeylanica (L.) Hook. which have diverse biological activities including PTP1B and α-glucosidase. The six ugonins (1-6) from the target plant showed significant neuraminidase inhibition. The inhibitory potencies were observed at a nanomolar level of 35-50 nM, which means they are 100 times more active than their corresponding mother compounds (eriodyctiol and luteolin). A detailed kinetic study revealed that all ugonins were reversible noncompetitive inhibitors. An in-depth investigation of the most potent compound 1 showed its time-dependent inhibition with the isomerization model having k 5 = 0.0103 min-1, k 6 = 0.0486 min-1, and K i app = 0.062 µM. The binding affinities (K sv) were agreed closely with our prediction based on the inhibitory potencies. Particularly, ugonin J (1) blocked the biofilm formation of E. coli dose-dependently up to 150 µM without the inhibition of bacteria. The major compounds (1-6) in the extract were characterized by UPLC-ESI-Q-TOF/MS.

16.
Microbiome ; 10(1): 3, 2022 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-34991725

RESUMEN

BACKGROUND: Host tp53 mutations are frequently found during the early stages of colitis-associated colorectal cancer (CAC), but whether such mutations induce gut microbiota dysbiosis and chronic intestinal inflammation that contributes to the development of CAC, remains unknown. RESULTS: We found that zebrafish tp53 mutant larvae exhibited elevated intestinal inflammation, by monitoring the NFκB activity in the mid-distal intestines of zebrafish larvae using an NFκB:EGFP transgenic reporter line in vivo as well as neutrophil infiltration into the intestine. This inflammation was due to dysbiotic gut microbiota with reduced diversity, revealed using both 16S rRNA amplicon sequencing and a germfree larva model. In this dysbiosis, Aeromonas spp. were aberrantly enriched as major pathobionts and exhibited the capacity for aggressive colonization in tp53 mutants. Importantly, the ex-germfree experiments supported the causality of the host tp53 mutation for inducing the inflammation. Transcriptome and high-performance liquid chromatography analyses of the host gastrointestinal tracts identified dysregulated sialic acid (SA) metabolism concomitant with increased host Neu5Gc levels as the key determinant of aberrant inflammation, which was reversed by the sialidase inhibitors oseltamivir and Philippin A. CONCLUSIONS: These results demonstrate a crucial role for host tp53 in maintaining symbiosis and immune homeostasis via SA metabolism. Disturbed SA metabolism via a tp53 mutation may be exploited by specific elements of the gut microbiome, eliciting both dysbiosis and inflammation. Manipulating sialometabolism may therefore provide an efficacious therapeutic strategy for tp53 mutation-induced dysbiosis, inflammation, and ultimately, related cancers. Video Abstract.


Asunto(s)
Disbiosis , Ácido N-Acetilneuramínico , Animales , Disbiosis/inducido químicamente , Inflamación , Mutación , Ácido N-Acetilneuramínico/efectos adversos , ARN Ribosómico 16S/genética , Pez Cebra
17.
Molecules ; 26(21)2021 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-34771010

RESUMEN

The aim of this study is to explore anti-inflammatory phytochemicals from B. chinensis based on the inhibition of pro-inflammatory enzyme, human neutrophil elastase (HNE) and anti-inflammatory activities in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage. Three stereoisomers of iridal-type triterpenoids (1-3) were isolated from the roots of B. chinensis and their stereochemistries were completely identified by NOESY spectra. These compounds were confirmed as reversible noncompetitive inhibitors against HNE with IC50 values of 6.8-27.0 µM. The binding affinity experiment proved that iridal-type triterpenoids had only a single binding site to the HNE enzyme. Among them, isoiridogermanal (1) and iridobelamal A (2) displayed significant anti-inflammatory effects by suppressing the expressions of pro-inflammatory cytokines, such as iNOS, IL-1ß, and TNF-α through the NF-κB pathway in LPS-stimulated RAW264.7 cells. This is the first report that iridal-type triterpenoids are considered responsible phytochemicals for anti-inflammatory effects of B. chinensis.


Asunto(s)
Antiinflamatorios/farmacología , Iridaceae/química , Elastasa de Leucocito/antagonistas & inhibidores , Extractos Vegetales/farmacología , Triterpenos/farmacología , Animales , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Humanos , Elastasa de Leucocito/metabolismo , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , Conformación Molecular , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Células RAW 264.7 , Triterpenos/química , Triterpenos/aislamiento & purificación
18.
Molecules ; 26(4)2021 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-33672673

RESUMEN

In this study, the changes in free amino acids of soybean leaves after ethylene application were characterized based on quantitative and metabolomic analyses. All essential and nonessential amino acids in soybean leaves were enhanced by fivefold (250 to 1284 mg/100 g) and sixfold (544 to 3478 mg/100 g), respectively, via ethylene application. In particular, it was found that asparagine is the main component, comprising approximately 41% of the total amino acids with a twenty-five fold increase (78 to 1971 mg/100 g). Moreover, arginine and branched chain amino acids (Val, Leu, and Ile) increased by about 14 and 2-5 times, respectively. The increase in free amino acid in stem was also similar to the leaves. The metabolites in treated and untreated soybean leaves were systematically identified by gas chromatography-mass spectrometry (GC-MS), and partial variance discriminant analysis (PLS-DA) scores and heat map analysis were given to understand the changes of each metabolite. The application of ethylene may provide good nutrient potential for soybean leaves.


Asunto(s)
Aminoácidos/metabolismo , Etilenos/metabolismo , Glycine max/química , Aminoácidos/química , Análisis Discriminante , Etilenos/química , Cromatografía de Gases y Espectrometría de Masas , Hojas de la Planta/química , Hojas de la Planta/metabolismo , Glycine max/metabolismo
19.
J Ethnopharmacol ; 272: 113935, 2021 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-33609726

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Caragana has a standing history of implementation in Traditional Chinese Medicine (TCM). Most species of this genus have been explored for multi-functional purposes, such as promoting blood circulation and curing neuralgia, fatigue, migraine, arthritis, and vascular hypertension (Meng et al., 2009). Among them, the well-known species C. sinica showed the most promising potential to increase the expression of ADAM10 among 313 tested medicinal plants, which is one of the promising approach for the treatment of Alzheimer's disease (AD). (Schuck et al., 2015). AIM OF THIS STUDY: The aim of this work is to explore ß-secretase inhibitory activity of compounds isolated from the aerial part of endemic Caragana balchaschensis (Kom.) Pojark. We provided a full characterization of their inhibitory mechanisms, binding affinities, and binding modes. MATERIALS AND METHODS: The isolation of quercetin derivatives was accomplished by various chromatographical approaches and their structures were annotated by spectroscopic analysis. The detailed kinetic behavior of ß-secretase inhibitors was determined by estimation of kinetic parameters (Km, Vmax, KI, and KIS). Binding affinities (KSV) and binding modes of inhibitors were elucidated by fluorescence quenching and molecular docking studies, respectively. RESULTS: O-methylated quercetins (2-7) were significantly effective in ß-secretase inhibition with IC50 ranging from 1.2 to 6.5 µM. The most active one (6) was 20-fold effective than the mother skeleton, quercetin. The O-methyl motif was a critical factor in ß-secretase inhibition: tri-O-methylated (1.2 µM) > di-O-methylated (3.5 µM) > mono-O-methylated (6.5 µM) > quercetin (25.2 µM). In the kinetic study, all quercetins (1-7) showed a noncompetitive inhibition, but glucoside ones (8 and 9) were mixed type I inhibitors. The binding affinities (KSV) were agreed with inhibitory potencies. The O-methylated quercetins were annotated as the most natural abundant metabolites in the aerial part by LC-ESI-TOF/MS. Binding modes of inhibitors to enzyme were elucidated by molecular docking experiments. CONCLUSION: This study disclosed that most of the major phenolic metabolites of the aerial part of C. balchaschensis are O-methylated quercetins, which have a significant inhibitory effect on ß-secretase, which is a critical factor for AD.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Caragana/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Quercetina/química , Quercetina/farmacología , Secretasas de la Proteína Precursora del Amiloide/química , Cromatografía Líquida de Alta Presión , Inhibidores Enzimáticos/aislamiento & purificación , Cinética , Metilación , Simulación del Acoplamiento Molecular , Componentes Aéreos de las Plantas/química , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Unión Proteica , Quercetina/aislamiento & purificación , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-Actividad , Espectrometría de Masas en Tándem
20.
Nat Prod Res ; 35(5): 880-883, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31084209

RESUMEN

Ikonnikovia kaufmanniana is an endemic plant of Kazakhstan of which phytochemical analysis has not been reported. The present study found out that this species enriched with antioxidant chemicals. Isolation and structural identification processes reveal twelve phenolic compounds (1-12) having dihydroflavanonol, flavonol, isoflavone and flavanol skeletons. The annotation of individual components in the extract was carried out by LC-ESI-MS/MS to represent a chemotaxonomic marker of the target plant. The antioxidant activities of all compounds were screened using three different radical sources (DPPH, ORAC, and hydroxyl radicals). Most compounds (1-11) had significant antioxidant activity against three radical sources, and their efficacies were found to differ by their functionality and skeleton. The potential of the isolated compounds in preventing oxidative damage of DNA was evaluated with pBR322 plasmid DNA. Compounds (1, 5, 7, and 8) had protective effects on DNA damaged with 80% efficacy at 60 µM concentration.


Asunto(s)
Daño del ADN , Fitoquímicos/análisis , Componentes Aéreos de las Plantas/química , Plumbaginaceae/química , Antioxidantes/química , Flavonoles/análisis , Fitoquímicos/química , Fitoquímicos/aislamiento & purificación , Extractos Vegetales/química , Plásmidos/genética , Polifenoles/análisis , Espectrometría de Masas en Tándem
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