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1.
Front Immunol ; 15: 1362642, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38745649

RESUMO

Hyperuricaemia (HUA) is a metabolic disorder characterised by high blood uric acid (UA) levels; moreover, HUA severity is closely related to the gut microbiota. HUA is also a risk factor for renal damage, diabetes, hypertension, and dyslipidaemia; however, current treatments are associated with detrimental side effects. Alternatively, Fangyukangsuan granules are a natural product with UA-reducing properties. To examine their efficacy in HUA, the binding of small molecules in Fangyukangsuan granules to xanthine oxidase (XOD), a key factor in UA metabolism, was investigated via molecular simulation, and the effects of oral Fangyukangsuan granule administration on serum biochemical indices and intestinal microorganisms in HUA-model rats were examined. Overall, 24 small molecules in Fangyukangsuan granules could bind to XOD. Serum UA, creatinine, blood urea nitrogen, and XOD levels were decreased in rats treated with Fangyukangsuan granules compared to those in untreated HUA-model rats. Moreover, Fangyukangsuan granules restored the intestinal microbial structure in HUA-model rats. Functional analysis of the gut microbiota revealed decreased amino acid biosynthesis and increased fermentation of pyruvate into short-chain fatty acids in Fangyukangsuan granule-treated rats. Together, these findings demonstrate that Fangyukangsuan granules have anti-hyperuricaemic and regulatory effects on the gut microbiota and may be a therapeutic candidate for HUA.


Assuntos
Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Microbioma Gastrointestinal , Hiperuricemia , Ácido Úrico , Animais , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Ratos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Masculino , Ácido Úrico/sangue , Xantina Oxidase/metabolismo , Ratos Sprague-Dawley
2.
J Asian Nat Prod Res ; 26(1): 130-138, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38217315

RESUMO

A new disaccharide glycoside, franchoside A (1), and 17 known compounds were isolated from the tubers of Arisaema franchetianum Engler. The chemical structure of the previously undescribed compound 1 was elucidated on the basis of detailed spectroscopic analyses. Compounds 1, 2, 6, 10, 14 and 18 showed significant cytotoxic activities at varying IC50 values in the range of 4.0-10.6 µM against five cancer cell lines. Compounds 8, 10, 13 and 17 (10 µM) exhibited moderate anti-inflammatory activities by inhibiting the NF-κB signaling pathway and the release of NO from RAW264.7 macrophages induced by lipopolysaccharide (LPS), while compounds 1, 9, 14, 15 and 16 showed weak anti-inflammatory activities.


Assuntos
Antineoplásicos , Arisaema , Glicosídeos/farmacologia , Glicosídeos/química , Linhagem Celular , Anti-Inflamatórios/farmacologia , Lipopolissacarídeos/farmacologia
3.
Zhongguo Zhong Yao Za Zhi ; 48(4): 978-984, 2023 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-36872268

RESUMO

The present study investigated the chemical constituents from the leaves of Craibiodendron yunnanense. The compounds were isolated and purified from the leaves of C. yunnanense by a combination of various chromatographic techniques including column chromatography over polyamide, silica gel, Sephadex LH-20, and reversed-phase HPLC. Their structures were identified by extensive spectroscopic analyses including MS and NMR data. As a result, 10 compounds, including melionoside F(1), meliosmaionol D(2), naringenin(3), quercetin-3-O-α-L-arabinopyranoside(4), epicatechin(5), quercetin-3'-glucoside(6), corbulain Ib(7), loliolide(8), asiatic acid(9), and ursolic acid(10), were isolated. Compounds 1 and 2 were two new compounds, and compound 7 was isolated from this genus for the first time. All compounds showed no significant cytotoxic activity by MTT assay.


Assuntos
Catequina , Ericaceae , Quercetina , Folhas de Planta , Cromatografia Líquida de Alta Pressão
4.
Signal Transduct Target Ther ; 8(1): 101, 2023 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-36894540

RESUMO

Tutin, an established toxic natural product that causes epilepsy in rodents, is often used as a tool to develop animal model of acute epileptic seizures. However, the molecular target and toxic mechanism of tutin were unclear. In this study, for the first time, we conducted experiments to clarify the targets in tutin-induced epilepsy using thermal proteome profiling. Our studies showed that calcineurin (CN) was a target of tutin, and that tutin activated CN, leading to seizures. Binding site studies further established that tutin bound within the active site of CN catalytic subunit. CN inhibitor and calcineurin A (CNA) knockdown experiments in vivo proved that tutin induced epilepsy by activating CN, and produced obvious nerve damage. Together, these findings revealed that tutin caused epileptic seizures by activating CN. Moreover, further mechanism studies found that N-methyl-D-aspartate (NMDA) receptors, gamma-aminobutyric acid (GABA) receptors and voltage- and Ca2+- activated K+ (BK) channels might be involved in related signaling pathways. Our study fully explains the convulsive mechanism of tutin, which provides new ideas for epilepsy treatment and drug development.


Assuntos
Calcineurina , Epilepsia , Animais , Camundongos , Calcineurina/genética , Calcineurina/metabolismo , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Epilepsia/genética , Picrotoxina , Receptores de GABA/metabolismo , Receptores de N-Metil-D-Aspartato , Convulsões/induzido quimicamente , Convulsões/genética
5.
J Ethnopharmacol ; 300: 115691, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36087844

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The plant Erigeron breviscapus (Vant.) Hand.-Mazz.,a Chinese herbal medicine with multiple pharmacological effects and clinical applications, has been traditionally used in the treatment of paralysis caused by stroke and joint pain from rheumatism by the Yi minority people of Southwest China for generations.However, its mechanism involves many factors and has not been fully clarified. AIM OF THE STUDY: Taking intestinal flora as the target, the protective effect of extract(breviscapine) of E. breviscapus on cerebral ischemia and its possible mechanism were discussed from the perspective of brain inflammatory pathway and intestinal CYP3A4, which depends on intestinal flora. MATERIALS AND METHODS: In this study, we first verified the binding ability between major active ingredient of Erigeron breviscapus and the core target TLR4 protein by molecular docking using Vina software.We established a rat model of cerebral ischemia-reperfusion injury in vivo.The neurological function of rats was scored by Bederson score table, the cerebral infarction volume was detected by TTC staining, and the serum NSE level was detected by ELASA. 16S rRNA sequencing was used to detect the intestinal flora of rats in each group.The expression levels of cerebral TLR4/MyD88/NF-κB and CYP3A4 mRNA and protein in different intestinal segments were detected by qRT-PCR and Western blot. RESULTS: Compared with the model group, the neurological injury score, infarct volume and serum NSE concentration of breviscapine low, medium and high dose groups and nimodipine groups decreased significantly. Meanwhile, breviscapine could significantly reduce the expression level of the TLR4/MyD88/NF-κB in brain tissue and CYP3A4 in different intestinal segments of rats with cerebral ischemia-reperfusion injury. In addition, breviscapine also significantly ameliorated intestinal flora dysbiosis of rats with cerebral ischemia-reperfusion injury. CONCLUSIONS: Breviscapine can protect rats from cerebral ischemia-reperfusion injury by regulating intestinal flora, inhibiting brain TLR4/MyD88/NF-κB inflammatory pathway and intestinal CYP3A4 expression.


Assuntos
Isquemia Encefálica , Medicamentos de Ervas Chinesas , Erigeron , Microbioma Gastrointestinal , Traumatismo por Reperfusão , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Erigeron/genética , Erigeron/metabolismo , Flavonoides , Simulação de Acoplamento Molecular , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Nimodipina/farmacologia , RNA Mensageiro/metabolismo , RNA Ribossômico 16S , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
6.
J Asian Nat Prod Res ; 25(7): 617-626, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36300525

RESUMO

One new taraxastane-type triterpenoid, three new grayanane-type diterpenoids (2 - 4), and 12 known compounds (5 - 16) were isolated from the leaves of Craiobiodendron yunnanens W. W. Smith. The structures of these compounds were elucidated on the basis of their spectroscopic data and chemical evidence. Compounds 1 and 8 exhibited partly anti-inflammatory activity based on the inhibition of NF-κB activity in SW480 cells at 10 µM with inhibition ratios of 60.53 and 59.20%, respectively. Compounds 10 and 13 showed excellent cytotoxicity against human leukemia cell (MV4-11) at 10 µM with inhibition ratios of 43.02 and 49.11%, respectively.


Assuntos
Diterpenos , Ericaceae , Humanos , Terpenos/farmacologia , Estrutura Molecular , Ericaceae/química , Folhas de Planta/química , Diterpenos/farmacologia , Diterpenos/química
7.
Phytochemistry ; 203: 113370, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35977602

RESUMO

Four undescribed flavonoid glucosides (iridins B-C, tectoridin A and ampelopsinin A); one undescribed phenolic glucoside (diplostephioside B); one undescribed phenolic compound (phenanthrenetriol A); and seventeen known compounds were isolated from the rhizomes of Iris domestica. The chemical structures of the undescribed compounds were established by spectroscopic/spectrometric data interpretation using HRESIMS, NMR, and ECD. Tectoridin A, nigricin A and naringenin exhibited anti-inflammatory activities with inhibition rates of 53.71%, 57.68% and 88.71%, respectively, against the NF-κB signaling pathway at a concentration of 10 µM. 4'-O-methylnyasol (10 µM) exhibited 84.91% antiproliferative activity against the K562 human leukemia cell line with an IC50 value of 4.20 µM.


Assuntos
Antineoplásicos , Gênero Iris , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Flavonoides/análise , Glucosídeos/química , Humanos , Gênero Iris/química , Estrutura Molecular , NF-kappa B , Fenóis , Rizoma/química
8.
Oxid Med Cell Longev ; 2022: 1198607, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35993026

RESUMO

Endothelial cell senescence is the main risk factor contributing to vascular dysfunction and the progression of aging-related cardiovascular diseases. However, the relationship between endothelial cell metabolism and endothelial senescence remains unclear. The present study provides novel insight into fatty acid metabolism in the regulation of endothelial senescence. In the replicative senescence model and H2O2-induced premature senescence model of primary cultured human umbilical vein endothelial cells (HUVECs), fatty acid oxidation (FAO) was suppressed and fatty acid profile was disturbed, accompanied by downregulation of proteins associated with fatty acid uptake and mitochondrial entry, in particular the FAO rate-limiting enzyme carnitine palmitoyl transferase 1A (CPT1A). Impairment of fatty acid metabolism by silencing CPT1A or CPT1A inhibitor etomoxir facilitated the development of endothelial senescence, as implied by the increase of p53, p21, and senescence-associated ß-galactosidase, as well as the decrease of EdU-positive proliferating cells. In the contrary, rescue of FAO by overexpression of CPT1A or supplement of short chain fatty acids (SCFAs) acetate and propionate ameliorated endothelial senescence. In vivo, treatment of acetate for 4 weeks lowered the blood pressure and alleviated the senescence-related phenotypes in aortas of Ang II-infused mice. Mechanistically, fatty acid metabolism regulates endothelial senescence via acetyl-coenzyme A (acetyl-CoA), as implied by the observations that suppression of acetyl-CoA production using the inhibitor of ATP citrate lyase NDI-091143 accelerated senescence of HUVECs and that supplementation of acetyl-CoA prevented H2O2-induced endothelial senescence. Deficiency of acetyl-CoA resulted in alteration of acetylated protein profiles which are associated with cell metabolism and cell cycle. These findings thus suggest that improvement of fatty acid metabolism might ameliorate endothelial senescence-associated cardiovascular diseases.


Assuntos
Acetilcoenzima A , Doenças Cardiovasculares , Ácidos Graxos , Acetilcoenzima A/metabolismo , Acetilação , Animais , Doenças Cardiovasculares/metabolismo , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Senescência Celular , Ácidos Graxos/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Camundongos , Oxirredução
9.
J Asian Nat Prod Res ; 24(10): 935-944, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36000737

RESUMO

A pair of stilbenes with γ-lactam unit [(+)-1 and (-)-1], a new phenolic glucoside (2), and a new isoflavone glucoside (3), together with two known compounds (4-5) were isolated from the rhizomes of Belamcanda chinensis. The chemical structures of the undescribed compounds were elucidated on the basis of detailed spectroscopic analyses. Compounds 1, 4, and 5 (10 µM) exhibited anti-inflammatory activities with inhibition rates of 30.46%, 60.34%, and 37.91%, respectively, against the NF-κB signaling pathway.


Assuntos
Iridaceae , Gênero Iris , Estilbenos , Rizoma/química , Iridaceae/química , Estilbenos/farmacologia , Estrutura Molecular , Fenóis/farmacologia , Fenóis/química , Glucosídeos/farmacologia
10.
Angew Chem Int Ed Engl ; 60(31): 17131-17137, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34008286

RESUMO

Targeted covalent inhibitors have re-emerged as validated drugs to overcome acquired resistance in cancer treatment. Herein, by using a carbonyl boronic acid (CBA) warhead, we report the structure-based design of BCR-ABL inhibitors via reversible covalent targeting of the catalytic lysine with improved potency against both wild-type and mutant ABL kinases, especially ABLT315I bearing the gatekeeper residue mutation. We show the evolutionarily conserved lysine can be targeted selectively, and the selectivity depends largely on molecular recognition of the non-covalent pharmacophore in this class of inhibitors, probably due to the moderate reactivity of the warhead. We report the first co-crystal structures of covalent inhibitor-ABL kinase domain complexes, providing insights into the interaction of this warhead with the catalytic lysine. We also employed label-free mass spectrometry to evaluate off-targets of our compounds at proteome-wide level in different mammalian cells.


Assuntos
Desenho de Fármacos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Lisina/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Lisina/síntese química , Lisina/química , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química
11.
Chembiochem ; 20(10): 1292-1296, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30648790

RESUMO

Fluorescent natural products are a rich source of drugs and chemical probes, but their innate fluorescence can interfere with fluorescence-based screening assays. Caspase-8 is a key player in apoptosis, its inhibition having been found to be beneficial for treatment of inflammatory and neurodegenerative diseases. Small-molecular inhibitors of caspase-8 remain sparsely reported, however. In this study, we firstly developed a light-up probe based on an AIEgen and capable of targeting caspase-8. This fluorescent dye has a Stokes shift of 200 nm, which could allow the innate fluorescence signals of natural products to be avoided. On screening a library of 86 fluorescent natural products, we found for the first time that gossypol showed potent inhibition of caspase-8 in vitro and in situ. This unique light-up probe, coupled with colored natural products, could represent an efficient approach to hit discovery for druggable targets.


Assuntos
Produtos Biológicos/farmacologia , Caspase 8/metabolismo , Inibidores de Caspase/farmacologia , Corantes Fluorescentes/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Produtos Biológicos/química , Inibidores de Caspase/química , Fluorescência , Corantes Fluorescentes/química , Gossipol/química , Gossipol/farmacologia , Células HeLa , Humanos , Bibliotecas de Moléculas Pequenas/química , Estereoisomerismo
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