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1.
J Am Chem Soc ; 146(18): 12723-12733, 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38654452

RESUMEN

Enfumafungin-type antibiotics, represented by enfumafungin and fuscoatroside, belong to a distinct group of triterpenoids derived from fungi. These compounds exhibit significant antifungal properties with ibrexafungerp, a semisynthetic derivative of enfumafungin, recently gaining FDA's approval as the first oral antifungal drug for treating invasive vulvar candidiasis. Enfumafungin-type antibiotics possess a cleaved E-ring with an oxidized carboxyl group and a reduced methyl group at the break site, suggesting unprecedented C-C bond cleavage chemistry involved in their biosynthesis. Here, we show that a 4-gene (fsoA, fsoD, fsoE, fsoF) biosynthetic gene cluster is sufficient to yield fuscoatroside by heterologous expression in Aspergillus oryzae. Notably, FsoA is an unheard-of terpene cyclase-glycosyltransferase fusion enzyme, affording a triterpene glycoside product that relies on enzymatic fusion. FsoE is a P450 enzyme that catalyzes successive oxidation reactions at C19 to facilitate a C-C bond cleavage, producing an oxidized carboxyl group and a reduced methyl group that have never been observed in known P450 enzymes. Our study thus sets the important foundation for the manufacture of enfumafungin-type antibiotics using biosynthetic approaches.


Asunto(s)
Antifúngicos , Antifúngicos/química , Antifúngicos/farmacología , Antifúngicos/metabolismo , Aspergillus oryzae/enzimología , Aspergillus oryzae/metabolismo , Familia de Multigenes , Triterpenos/química , Triterpenos/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo
2.
J Nat Prod ; 2024 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-39194958

RESUMEN

ortho-Quinone methides (o-QMs) are a class of highly reactive intermediates that serve as important nonisolable building blocks (NBBs) in organic synthesis and small-molecule library construction. Because of their instability and nonisolability, most reported o-QMs are generated through in situ chemical synthesis, and only a few natural o-QMs have been reported due to the lack of directed discovery strategies. Herein, a new natural o-QM precursor (trichophenol A, 2) was identified from the fungal strain of Trichoderma sp. AT0167 through genome mining, which was generated by trilA (nonreducing polyketide synthase) and trilB (2-oxoglutarate dependent dioxygenase). Combinatorial biosynthesis via two other known NRPKS genes with trilA and trilB was performed, leading to the generation of five new trichophenol o-QM oligomers (trichophenols D-H, 5-9). The strategy combining genome mining with combinatorial biosynthesis not only targetedly uncovered a new natural o-QM precursor but also produced various new molecules through oligomerization of the new o-QM and its designated o-QM acceptors without chemical synthesis and isolation of intermediates, which was named NBB genome mining-combinatorial biosynthesis strategy for o-QM molecule library construction. This study provides a new strategy for the targeted discovery of natural o-QMs and small-molecule library construction with natural o-QMs.

3.
Curr Osteoporos Rep ; 2024 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-39235563

RESUMEN

PURPOSE OF REVIEW: Traditional Chinese Medicine has a unique system to diagnose and treat bone diseases with symptoms similar to those of osteoporosis. Sambucus williamsii Hance (SWH), a folk medicine in northern part of China for fractures healing and pain alleviation, has been demonstrated to exert bone anabolic effects in ovariectomized (OVX) rat and mice models in our previous studies. Lignans were identified to be the main bioactive fractions of SWH. However, pharmacokinetics study showed that the levels of lignan were too low to be detected in rat serum even upon taking 15 times of the effective dose of lignan-rich fraction from SWH. We hypothesize that lignans from SWH might exert its bone protective effect via the gut microbiome. RECENT FINDINGS: Our study revealed that the lignan-rich fraction of SWH did not influence the diversity of gut microbiota in OVX rats, but significantly increased the abundance of a few phyla, in particular, the restoration of the abundance of several genera that was directly correlated with bone mineral density (BMD). In addition, a subsequent metabolomic study indicated that serotonin, a neurotransmitter synthesized in the intestine and influenced by gut microbiota, may be involved in mediating the bone protective action of the lignans. Gut-derived serotonin is thought to inhibit bone growth. Based on this finding, several inhibitors that suppressed the synthesis of serotonin were identified from the lignans of SWH. Our studies suggested that microbiome is an indispensable factor for lignans derived from S. willimasii to exert bone beneficial effects.

4.
J Asian Nat Prod Res ; : 1-9, 2024 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-38247111

RESUMEN

Rauvolfia dichotoma, a shrub of Apocynaceae, was collected from the Islands of SAO Tome and Principe and cultivated locally for medicinal purpose. Phytochemical investigation of 95% ethanol extract from the stems and leaves of R. dichotoma led to the isolation of two new Nb-oxide indole alkaloids, namely Nb-oxide-mitoridine (1) and Nb-oxide-raucaffricine (2), together with two known alkaloids (3-4) and eleven known lignans (5-15). Their chemical structures were elucidated by extensive NMR and HR-ESI-MS data analysis. All compounds (except 13) were tested for their ß-hematin inhibitory activity. Compounds 2, 4, 14, and 15 showed certain inhibitory activity, indicating that they may have an antimalarial effect.

5.
J Asian Nat Prod Res ; : 1-28, 2024 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-38958647

RESUMEN

The SwissTargetPrediction was employed to predict the potential drug targets of the active component of Si-Miao-Yong-An decoction (SMYAD). The therapeutic targets for HF were searched in the Genecard database, and Cytoscape3.9.1 software was used to construct the "drug-component-target-disease network" diagram. In addition, the String platform was used to construct Protein-Protein Interaction (PPI) network, and the DAVID database was used for GO and KEGG analysis. AutoDockTools-1.5.6 software was used for molecular docking verification. Network pharmacology studies have shown that AKT 1, ALB, and CASP 3 are the key targets of action of SMYAD against heart failure. The active compounds are quercetin and kaempferol.

6.
Angew Chem Int Ed Engl ; : e202407895, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38949843

RESUMEN

The diterpene synthase AfAS was identified from Aspergillus fumigatiaffinis. Its amino acid sequence and-according to a structural model-active site architecture are highly similar to those of the fusicocca-2,10(14)-diene synthase PaFS, but AfAS produces a structurally much more complex diterpene with a novel 6-5-5-5 tetracyclic skeleton called asperfumene. The cyclisation mechanism of AfAS was elucidated through isotopic labelling experiments and DFT calculations. The reaction cascade proceeds in its initial steps through similar intermediates as for the PaFS cascade, but then diverges through an unusual vicinal deprotonation-reprotonation process that triggers a skeletal rearrangement at the entrance to the steps leading to the unique asperfumene skeleton. The structural model revealed only one major difference between the active sites: The PaFS residue F65 is substituted by I65 in AfAS. Intriguingly, site-directed mutagenesis experiments with both diterpene synthases revealed that position 65 serves as a bidirectional functional switch for the biosynthesis of tetracyclic asperfumene versus structurally less complex diterpenes.

7.
Org Biomol Chem ; 21(20): 4309-4318, 2023 05 24.
Artículo en Inglés | MEDLINE | ID: mdl-37171256

RESUMEN

In fungi, there is a rare group of natural products harboring the 2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromene skeleton, represented by xyloketal B, which display a wide range of biological activities and have drawn significant attention. In this work, four new analogues simpliketals A-D (1-4), as well as two other new compounds simplilactones A and B (5 and 6), were isolated from Simplicillium sp. AHK071-01. Their structures were elucidated by extensive NMR spectroscopic methods, 13C NMR calculation, single-crystal X-ray diffraction, and ECD calculation. In addition, five known compounds (7-11) including alboatrin (7) were also obtained. Based on the structural similarity of the above compounds, we inferred that compounds 5, 6, and 8-11 might be biosynthetically related with 1-4 and 7, which allowed us to propose an alternative biosynthetic route to generate the furan-fused chromene skeleton of this class of compounds, instead of a previously presumed polyketide-terpenoid hybrid pathway. Finally, cytotoxicity assays showed that 1-4 exhibited weak inhibitory activity on PANC-1 cells and that 2 and 3 possessed moderate activity against SH-SY5Y cells.


Asunto(s)
Hypocreales , Neuroblastoma , Humanos , Benzopiranos/química , Estructura Molecular , Furanos
8.
Org Biomol Chem ; 21(4): 851-857, 2023 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-36602159

RESUMEN

Fernane-type triterpenoids are a small group of natural products mainly found in plants and fungi with a wide range of biological activities. Polytolypin is a representative fernane-type triterpenoid from fungi and possesses potent antifungal activity. So far, biosynthesis of fungal-derived fernane-type triterpenoids has not been characterized, which hinders the expansion of their structural diversity using biosynthetic approaches. Herein, we identified the biosynthetic gene cluster of polytolypin and elucidated its biosynthetic pathway through heterologous expression in Aspergillus oryzae NSAR1, which involves a new triterpene cyclase for the biosynthesis of the hydrocarbon skeleton motiol, followed by multiple oxidations via three P450 enzymes. Moreover, two new triterpene cyclases for the biosynthesis of two other fernane-type skeletons isomotiol and fernenol were identified from fungi, and were individually co-expressed with the three P450 enzymes involved in polytolypin biosynthesis. These studies led to the generation of 13 fernane-type triterpenoids including eight new compounds, and two of them showed stronger antifungal activity towards Candida albicans FIM709 than polytolypin.


Asunto(s)
Antifúngicos , Triterpenos , Antifúngicos/farmacología , Triterpenos/farmacología , Triterpenos/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Triterpenos Pentacíclicos , Vías Biosintéticas/genética
9.
J Sep Sci ; 46(2): e2200723, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36401831

RESUMEN

Codonopsis radix was commonly used as food materials or herbal medicines in many countries. However, the comprehensive analysis of chemical constituents, and in vivo xenobiotics of Codonopsis radix remain unclear. In the present study, an integrated strategy with feature-based molecular networking using ultra-high-performance liquid chromatography coupled with mass spectrometry was established to systematically screen the chemical constituents and the in vivo xenobiotics of Codonopsis radix. A step-by-step manner based on a composition database, visual structure classification, discriminant ions, and metabolite software prediction was proposed to overcome the complexities due to the similar structure of chemical constituents and metabolites of Codonopsis radix. As a result, 103 compounds were tentatively characterized, 20 of which were identified by reference standards. Besides, a total of 50 xenobiotics were detected in vivo, including 26 prototypes and 24 metabolites, while the metabolic features of the pyrrolidine alkaloids were elucidated for the first time. The metabolism reactions of pyrrolidine alkaloids and sesquiterpene lactones included oxidation, methylation, hydration, hydrogenation, demethylation, glucuronidation, and sulfation. This study provided a generally applicable approach to the comprehensive investigation of the chemical and metabolic profile of traditional Chinese medicine and offered reasonable guidelines for further screening of quality control indicators and pharmacodynamics mechanism of Codonopsis radix.


Asunto(s)
Alcaloides , Codonopsis , Medicamentos Herbarios Chinos , Ratas , Animales , Medicamentos Herbarios Chinos/análisis , Codonopsis/química , Codonopsis/metabolismo , Ratas Sprague-Dawley , Cromatografía Líquida de Alta Presión/métodos , Xenobióticos/metabolismo , Espectrometría de Masas/métodos , Alcaloides/química , Pirrolidinas
10.
J Sep Sci ; 46(17): e2300331, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37438987

RESUMEN

An efficient strategy for the identification of potential nephroprotective substances in Zhu-Ling decoction has been established with the integration of absorbed components characterization, pharmacokinetics, and activity evaluation. A qualitative method was developed to characterize the chemical constituents absorbed components in vivo of Zhu-Ling decoction by using ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry. A quantitative method was established and validated for the simultaneous determination of eight compounds in rat plasma by using ultra-performance liquid chromatography-triple quadruple tandem mass spectrometry. Finally, the nephroprotective activities of absorbed components with high exposure were assessed by cell survival rate, superoxide dismutase, and malondialdehyde activities in hydrogen peroxide-induced Vero cells. As a result, 111 compounds in Zhu-Ling decoction and 36 absorbed components were identified in rat plasma and urine, and poricoic acid A, poricoic acid B, alisol A, 16-oxo-alisol A, and dehydro-tumulosic acid had high exposure levels in rat plasma. Finally, poricoic acid B, poricoic acid A, 16-oxo-alisol A, and dehydro-tumulosic acid showed remarkable nephroprotective activity against Vero cells damage induced by hydrogen peroxide. Besides, superoxide dismutase and malondialdehyde activities were obviously regulated in hydrogen peroxide-induced Vero cells by treatment with the four compounds mentioned above. Therefore, these four compounds were considered to be effective substances of Zhu-Ling decoction due to their relatively high exposure in vivo and biological activity. This study provided a chemical basis for the action mechanism of Zhu-Ling decoction in the treatment of chronic kidney diseases.


Asunto(s)
Medicamentos Herbarios Chinos , Triterpenos , Chlorocebus aethiops , Ratas , Animales , Peróxido de Hidrógeno , Células Vero , Espectrometría de Masas/métodos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Cromatografía Líquida de Alta Presión/métodos
11.
Molecules ; 28(3)2023 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-36770929

RESUMEN

Prostate adenocarcinoma (PRAD) is the most frequent malignancy, and is the second leading cause of death due to cancer in men. Thus, new prognostic biomarkers and drug targets for PRAD are urgently needed. As we know, nuclear receptor Nur77 is important in cancer development and changes in the tumor microenvironment; whereas, the function of Nur77 in PRAD remains to be elucidated. The TCGA database was used to explore the Nur77 expression and its role in the prognosis of PRAD. It was shown that Nur77 was down regulated in PRAD, and low Nur77 expression was correlated with advanced clinical pathologic characteristics (high grade, histological type, age) and poor prognosis. Furthermore, key genes screening was examined by univariate Cox analysis and Kaplan-Meier survival. Additionally, Nur77 was closely related to immune infiltration and some anti-tumor immune functions. The differentially expressed genes (DEGs) were presented by protein-protein interaction (PPI) network analysis. Therefore, the expression level of Nur77 might help predict the survival of PRAD cases, which presents a new insight and a new target for the treatment of PRAD. In vitro experiments verified that natural product malayoside targeting Nur77 exhibited significant therapeutic effects on PRAD and largely induced cell apoptosis by up-regulating the expression of Nur77 and its mitochondrial localization. Taken together, Nur77 is a prognostic biomarker for patients with PRAD, which may refresh the profound understanding of PRAD individualized treatment.


Asunto(s)
Adenocarcinoma , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares , Neoplasias de la Próstata , Humanos , Masculino , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Biomarcadores , Pronóstico , Próstata , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Microambiente Tumoral/genética , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética
12.
J Nat Prod ; 85(10): 2312-2331, 2022 10 28.
Artículo en Inglés | MEDLINE | ID: mdl-36137221

RESUMEN

Twenty new malabaricane triterpenoids, astramalabaricosides A-T (1-20), were isolated from the roots of Astragalus membranaceus var. mongholicus (Astragali Radix). Their structures were determined by spectroscopic analysis, and the use of the circular dichroism exciton chirality method, quantum chemical calculations, and chemical methods. Malabaricane triterpenoids, an unusual group with the 6-6-5-tricyclic core, are distributed in plants (e.g., Simaroubaceae, Polypodiaceae, and Fabaceae), a marine sponge, and fungi, and their number obtained to date is limited. Compounds 1-20 were characterized as glycosides with a highly oxygenated side chain, and 13-20 were the first cyclic carbonate derivatives among the malabaricane triterpenoids. The stereocluster formed from the continuous hydroxylated chiral carbons in each highly oxygenated side chain and the 6-6-5-tricyclic core system were entirely segregated, and the independent identification of their stereoconfigurations required considerable effort. The migratory inhibitory and antiproliferative activities of 1-20 were evaluated by wound-healing and cell-viability assays, respectively. Most compounds showed significant migratory inhibitory activity, and a preliminary structure-activity relationship was developed. Malabaricane triterpenoids are being reported in the genus Astragalus for the first time.


Asunto(s)
Planta del Astrágalo , Triterpenos , Astragalus propinquus/química , Triterpenos/farmacología , Triterpenos/análisis , Raíces de Plantas/química
13.
J Sep Sci ; 45(13): 2177-2189, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35478323

RESUMEN

In the present study, a specific and sensitive approach using ultra-high-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry was developed and validated for the quantitative analysis of 14 constituents in rat plasma, liver, and heart. The method was fully validated and successfully applied to pharmacokinetic, hepatic disposition, and heart tissue distribution studies of 14 compounds after the oral administration of Qi-Li-Qiang-Xin capsule. Ginsenoside Rb1, alisol A, astragaloside IV, and periplocymarin were found to be highly exposed in rat plasma, while toxic components such as hypaconitine, mesaconitine, and periplocin had low circulation levels in vivo. Moreover, sinapine thiocyanate, neoline, formononetin, calycosin, and alisol A exhibited significant liver first-pass effects. Notably, high levels of alisol A, periplocymarin, benzoylmesaconine, and benzoylhypaconine were observed in the heart. Based on high exposure and appropriate pharmacokinetic features in the systemic plasma and heart, astragaloside IV, ginsenoside Rb1, periplocymarin, benzoylmesaconine, benzoylhypaconine, and alisol A can be considered as the main potentially effective components. Ultimately, the results provide relevant information for discovery of effective substances, as well as further anti-heart failure action mechanism investigations of Qi-Li-Qiang-Xin capsule.


Asunto(s)
Medicamentos Herbarios Chinos , Espectrometría de Masas en Tándem , Administración Oral , Animales , Cromatografía Líquida de Alta Presión/métodos , Medicamentos Herbarios Chinos/análisis , Hígado/química , Ratas , Espectrometría de Masas en Tándem/métodos , Distribución Tisular
14.
J Org Chem ; 86(16): 11177-11188, 2021 08 20.
Artículo en Inglés | MEDLINE | ID: mdl-34043349

RESUMEN

A secondary metabolites investigation on Biscogniauxia sp. 71-10-1-1 was carried out, which led to the obtention of nine new diisoprenyl-cyclohexene/ane-type meroterpenoids (1-9) and two new isoprenylbenzoic acid-type meroterpeniods (10-11). The structures of these isolates were established on the basis of multispectroscopic analyses, ECD, and 13C chemical shifts calculations, and single-crystal X-ray diffraction. Among them, biscognin A (1) is the first diisoprenyl-cyclohexene-type meroterpenoid with a unique 2-isopropyl-6'-methyloctahydro-1'H-spiro[cyclopropane-1,2'-naphthalene] skeleton. Biscognienyne F (5) is the first diisoprenyl-cyclohexene-type meroterpenoid with a cyclic carbonate. The anti-inflammatory assays of the majority of compounds were evaluated, which exhibited that compounds 3 and 5 can obviously inhibit pro-inflammatory cytokines TNF-α and IL-6 productions. This is the first report for diisoprenyl-cyclohexene-type meroterpenoids with anti-inflammatory activity. Moreover, the possible biogenetic pathways of the majority of compounds (1-5) are proposed.


Asunto(s)
Ciclohexenos , Terpenos , Antiinflamatorios/farmacología , Vías Biosintéticas , Cristalografía por Rayos X , Ciclohexenos/farmacología , Terpenos/farmacología
15.
Bioorg Med Chem Lett ; 38: 127859, 2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33609662

RESUMEN

A pair of undescribed enantiomers, (±) ficusflavonid A (1a/1b), along with five known analogues, were isolated from the roots of Ficus hirta. Their structures were determined by the analysis of extensive spectroscopic data (including UV, IR, HRESIMS and NMR). Two enantiomers (1a and 1b) were successfully separated by chiral chromatographic column and their absolute configurations were assigned by the comparison of experimental and calculated ECD data. The cytotoxicity of all the isolates against HeLa, MCF-7, HepG2 and H460 cell lines were evaluated by MTT assay. Among them, 4 suppressed the proliferation of HeLa cells with the IC50 value of 28.88 µM. Furthermore, the apoptotic effect of 4 on HeLa cells and the level of several crucial proteins in AKT/MAPKs signaling pathways were analyzed by flow cytometer and western blot assay. As a result, 4 induced HeLa cell apoptosis in a dose dependent manner and significantly increased the protein levels of p-JNK and p-p38, whereas distinctly reduced the expression of p-AKT, and p-ERK. Thus, compound 4 might induce HeLa cells apoptosis via MAPK and AKT signaling pathways, which could be considered as a potential leading compound for the development of anticancer drugs.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Ficus/química , Flavonoides/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Flavonoides/síntesis química , Flavonoides/química , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Estructura Molecular , Proteínas Proto-Oncogénicas c-akt/metabolismo , Relación Estructura-Actividad
16.
Bioorg Chem ; 116: 105307, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34482167

RESUMEN

Eight new (1-7 and 15) and 18 known (8-14 and 16-26) phenylpropanoid derivatives were isolated from the fruits of Lycium ruthenicum Murr. (black wolfberry). Their structures were determined by comprehensive spectroscopic analyses, chemical methods, and comparisons of spectroscopic data. Four known compounds (16, 17, 24, and 26) were firstly isolated from the genus Lycium. Interestingly, compounds 1/2 and 4/5 were isolated as two pairs of inseparable anomers owing to the tautomerism of the free hemiacetal at C-1'' in solution. The antioxidant, α-glucosidase inhibitory, and acetylcholinesterase (AChE) inhibitory activities of compounds 1-26 were evaluated. Some compounds possessed DPPH radical scavenging activity, and all compounds (1-26) exhibited different levels of oxygen radical absorbance capacity (ORAC). One compound displayed α-glucosidase inhibitory activity with potency close to that of the positive control (acarbose).


Asunto(s)
Antioxidantes/farmacología , Inhibidores de la Colinesterasa/farmacología , Frutas/química , Inhibidores de Glicósido Hidrolasas/farmacología , Lycium/química , Propionatos/farmacología , Acetilcolinesterasa/metabolismo , Antioxidantes/síntesis química , Antioxidantes/química , Compuestos de Bifenilo/antagonistas & inhibidores , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Inhibidores de Glicósido Hidrolasas/síntesis química , Inhibidores de Glicósido Hidrolasas/química , Estructura Molecular , Picratos/antagonistas & inhibidores , Propionatos/síntesis química , Propionatos/química , Relación Estructura-Actividad , alfa-Glucosidasas/metabolismo
17.
Exp Cell Res ; 395(1): 112186, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32698024

RESUMEN

8-prenylgenistein (8PG) was previously reported to exert stronger osteogenic activity than genistein, a well-known soy phytoestrogen. However, the molecular mechanism underlying the actions of 8PG on osteoblasts was far from clear. In the present study, the osteogenic effects and mechanisms of 8PG and genistein were studied using human BMSC and murine pre-osteoblast MC3T3-E1 cells. Our results indicated that the stimulatory effects of 8PG and genistein on osteoblast differentiation were abolished by co-incubation with MPP (10-6 M, an ERα antagonist), but not PHTPP (10-6 M, an ERß antagonist). Molecular docking indicated that the binding mode of 8PG toward ERα was similar to that of genistein and therefore could not account for their differential osteogenic actions. In silico target profiling identified the involvement of glycogen synthase kinase-3ß (GSK-3ß), a key mediator of Wnt/ß-catenin pathway, in the actions of 8PG. However, instead of directly inhibiting GSK-3ß enzymatic activities, 8PG and genistein were found to induce GSK-3ß phosphorylation at Serine-9 in osteoblastic MC3T3-E1 cells. 8PG exerted more potent effects than genistein in stimulating expressions of LRP5, ß-catenin, Runx2, osteocalcin, alp, opg, major protein and gene markers involved in Wnt signaling pathway in MC3T3-E1 cells. Moreover, the inhibition of Wnt signaling by DKK1 could be restored by treatment with 8PG and genistein. However, 8PG, but not genistein, stimulated ERα-dependent ß-catenin protein expression in MC3T3-E1 cells. Furthermore, the increase in ALP activity, LRP5 and phospho-Akt/Akt expression by 8PG and genistein were abolished by co-treatment with LY294002 (10-5 M, a PI3K pathway inhibitor). Collectively, our results suggested that the osteogenic activities of 8PG was mediated by GSK-3ß phosphorylation through the induction of Wnt/ß-catenin and ERα-associated PI3K/Akt signaling.


Asunto(s)
Receptor alfa de Estrógeno/efectos de los fármacos , Genisteína/análogos & derivados , Osteogénesis/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Genisteína/metabolismo , Genisteína/farmacología , Humanos , Simulación del Acoplamiento Molecular/métodos , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo
18.
Biomed Chromatogr ; 35(12): e5177, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33998678

RESUMEN

Cimicifuga dahurica (Turcz.) Maxim, which is also regarded as the main origin of "Shengma" in the Chinese Pharmacopoeia, has been used as a cooling and detoxification agent for thousands of years. Our previous phytochemical investigations of C. dahurica extracts (CDEs) led to the isolation of a series of 9,19-cycloalkane triterpenoids and phenolic acids showing a potential anti-inflammatory activity. However, the chemical profiling of CDEs and the material basis of its anti-inflammatory effect in vivo has not been clarified. In the present study, the CDE chemical profile and prototype components in rat plasma were identified via ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. As a result, a total of 106 components were identified or tentatively characterized in CDEs, including 54 triterpenoids, 35 phenolic acids, eight amides and nine other type constituents (39 compounds were confirmed with the reference standards). In addition, 20 prototype components (15 triterpenoids and five phenolic acids) were identified in rat plasma, which potentially related to the anti-inflammatory effects of CDEs. Moreover, the anti-inflammatory activities of the main prototype components were further evaluated by their inhibitory effects on the production of NO, as well as the expressions of iNOS and COX-2 in lipopolysaccharide-stimulated RAW264.7 cells, which indicated that 9,19-cycloalkane triterpenoids may play an anti-inflammatory role by down-regulating the expression of iNOS.


Asunto(s)
Antiinflamatorios , Cimicifuga/química , Farmacología en Red/métodos , Extractos Vegetales , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Supervivencia Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas/métodos , Ratones , Extractos Vegetales/química , Extractos Vegetales/farmacología , Células RAW 264.7 , Ratas , Triterpenos/análisis , Triterpenos/química , Triterpenos/farmacología
19.
Biomed Chromatogr ; 35(6): e5072, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33453065

RESUMEN

Jin-hong tablets (JHTs), a well-known traditional Chinese patent medicine (TCPM), have been effectively used for the treatment of chronic superficial gastritis (CSG). The metabolic profile of TCPMs is performed to determine their bioactive components. In this study, a five-step strategy based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry and metabolynx™ software combined with mass defect filter technique was developed to delineate the metabolic profile of JHT in vivo. As a result, a total of 163 JHT-related xenobiotics (38 prototypes and 125 metabolites) were identified or tentatively characterized in rat biological samples, and the phase I and II metabolism processes mainly included demethylation, hydroxylation, sulfation, and glucuronidation. In addition, after oral administration of JHT, a large amount of alkaloid-related ingredients was detected in rat plasma samples, indicating that alkaloids may play an important role in the treatment of CSG with JHT. This study is beneficial for understanding the JHT's in vivo metabolic profiles and characteristics, which helps to reveal its in vivo effective components and provides a solid basis for further studies on its functional mechanism.


Asunto(s)
Alcaloides , Cromatografía Líquida de Alta Presión/métodos , Medicamentos Herbarios Chinos , Espectrometría de Masas en Tándem/métodos , Administración Oral , Alcaloides/análisis , Alcaloides/química , Alcaloides/metabolismo , Animales , Alcaloides de Berberina , Bilis/química , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/metabolismo , Heces/química , Flavonoides/análisis , Flavonoides/química , Flavonoides/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Comprimidos
20.
J Asian Nat Prod Res ; 23(8): 724-730, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34253100

RESUMEN

Three new flavonoid glycosides, embeliaflavosides A-C (1-3), together with eight known flavonoid glycosides (4-11), were isolated from the fruits of Embelia ribes. Their structures were established based on the analyses of spectroscopic data. Compounds 1-11 were evaluated for antioxidant and α-glucosidase inhibitory activities. The results revealed that compounds 1-11 owned significant ABTS radical scavenging activity with IC50 values of 2.52-9.78 µM, and DPPH scavenging activity with IC50 values of 7.56-26.47 µM, respectively. However, α-glucosidase inhibition assay indicated that all the isolates were inactive.[Formula: see text].


Asunto(s)
Embelia , Ribes , Antioxidantes/farmacología , Embelia/metabolismo , Flavonoides/farmacología , Frutas , Inhibidores de Glicósido Hidrolasas/farmacología , Glicósidos/farmacología , Estructura Molecular , Extractos Vegetales , Ribes/metabolismo , alfa-Glucosidasas/metabolismo
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