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1.
Int J Biol Sci ; 19(1): 294-310, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36594097

RESUMO

Acute kidney injury (AKI) is a pathological condition characterized by a rapid decrease in glomerular filtration rate and nitrogenous waste accumulation during hemodynamic regulation. Alisol B, from Alisma orientale, displays anti-tumor, anti-complement, and anti-inflammatory effects. However, its effect and action mechanism on AKI is still unclear. Herein, alisol B significantly attenuated cisplatin (Cis)-induced renal tubular apoptosis through decreasing expressions levels of cleaved-caspase 3 and cleaved-PARP and the ratio of Bax/Bcl-2 depended on the p53 pathway. Alisol B also alleviated Cis-induced inflammatory response (e.g. the increase of ICAM-1, MCP-1, COX-2, iNOS, IL-6, and TNF-α) and oxidative stress (e.g. the decrease of SOD and GSH, the decrease of HO-1, GCLC, GCLM, and NQO-1) through the NF-κB and Nrf2 pathways. In a target fishing experiment, alisol B bound to soluble epoxide hydrolase (sEH) as a direct cellular target through the hydrogen bond with Gln384, which was further supported by inhibition kinetics and surface plasmon resonance (equilibrium dissociation constant, K D = 1.32 µM). Notably, alisol B enhanced levels of epoxyeicosatrienoic acids and decreased levels of dihydroxyeicosatrienoic acids, indicating that alisol B reduced the sEH activity in vivo. In addition, sEH genetic deletion alleviated Cis-induced AKI and abolished the protective effect of alisol B in Cis-induced AKI as well. These findings indicated that alisol B targeted sEH to alleviate Cis-induced AKI via GSK3ß-mediated p53, NF-κB, and Nrf2 signaling pathways and could be used as a potential therapeutic agent in the treatment of AKI.


Assuntos
Injúria Renal Aguda , Cisplatino , Humanos , Cisplatino/toxicidade , NF-kappa B/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Apoptose , Rim/metabolismo , Estresse Oxidativo , Inflamação/tratamento farmacológico , Inflamação/metabolismo
2.
J Agric Food Chem ; 70(48): 15104-15115, 2022 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-36414003

RESUMO

18ß-Glycyrrhetinic acid (GA) is a triterpenoid possessing an anti-inflammatory activity in vivo, while the low bioavailability limits its application due to its intestinal accumulation. In order to investigate the metabolism of GA in intestinal microbes, it was incubated with human intestinal fungus Aspergillus niger RG13B1, finally leading to the isolation and identification of three new metabolites (1-3) and three known metabolites (4-6) based on 1D and 2D NMR and high-resolution electrospray ionization mass spectroscopy spectra. Metabolite 6 could target myeloid differentiation protein 2 (MD2) to suppress the activation of nuclear factor-kappa B (NF-κB) signaling pathway via inhibiting the nuclear translocation of p65 to downregulate its target proteins and genes in lipopolysaccharide (LPS)-mediated RAW264.7 cells. Molecular dynamics suggested that metabolite 6 interacted with MD2 through the hydrogen bond of amino acid residue Arg90. These findings demonstrated that metabolite 6 could serve as a potential candidate to develop the new inhibitors of MD2.

3.
Phytomedicine ; 107: 154380, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36150346

RESUMO

BACKGROUND: Acute lung injury (ALI) is a severe respiratory disease characterized by diffuse lung interstitial and respiratory distress and pulmonary edema with a mortality rate of 35%-40%. Inula japonica Thunb., known as "Xuan Fu Hua" in Chinese, is a traditional Chinese medicine Inulae Flos to use for relieving cough, eliminating expectorant, and preventing bacterial infections in the clinic, and possesses an anti-pulmonary fibrosis effect. However, the effect and action mechanism of I. japonica on ALI is still unclear. PURPOSE: This study aimed to investigate the protective effect and underlying mechanism of total flavonoids of I. japonica (TFIJ) in the treatment of ALI. STUDY DESIGN AND METHODS: A mouse ALI model was established through administration of LPS by the intratracheal instillation. Protective effects of TFIJ in the inflammation and oxidative stress were studied in LPS-induced ALI mice based on inflammatory and oxidative stress factors, including MDA, MPO, SOD, and TNF-α. Lipid metabolomics, bioinformatics, Western blot, quantitative real-time PCR, and immunohistochemistry were performed to reveal the potential mechanism of TFIJ in the treatment of ALI. RESULTS: TFIJ significantly alleviated the interstitial infiltration of inflammatory cells and the collapse of the alveoli in LPS-induced ALI mice. Lipid metabolomics demonstrated that TFIJ could significantly affect the CYP2J/sEH-mediated arachidonic acid metabolism, such as 11,12-EET, 14,15-EET, 8,9-DHET, 11,12-DHET, and 14,15-DHET, revealing that sEH was the potential target of TFIJ, which was further supported by the recombinant sEH-mediated the substrate hydrolysis in vitro (IC50 = 1.18 µg/ml). Inhibition of sEH by TFIJ alleviated the inflammatory response and oxidative stress via the MAPK, NF-κB, and Nrf2 signaling pathways. CONCLUSION: These results demonstrated that TFIJ could suppress the sEH activity to stabilize the level of EETs, allowing the alleviation of the pathological course of lung injury in LPS-treated mice, which suggested that TFIJ could serve as the potential agents in the treatment of ALI.


Assuntos
Lesão Pulmonar Aguda , Inula , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Animais , Ácido Araquidônico/metabolismo , Expectorantes/efeitos adversos , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Lipopolissacarídeos/farmacologia , Pulmão , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
4.
Phytochemistry ; 203: 113339, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35961409

RESUMO

Ganoderma lucidum is a famous edible and medicinal fungus. Through a bioactive phytochemical investigation of the ethanolic extracts of the fruiting bodies of G. lucidum, twenty-nine triterpenoids, including eleven previously undescribed triterpenoids, were isolated and characterized based on spectroscopic data. The inhibitory effects of all the triterpenes against fatty acid amide hydrolase (FAAH) were found to be in the range of 30-60% at 100 µM. Methyl ganoderate A displayed the strongest inhibitory activity (61%) against FAAH. Furthermore, all compounds displayed no cytotoxicity against LOVO and MCF-7 human cancer cells. Hence, our present study provides information about G. lucidum as a functional food or pharmaceutical supplement for the treatment of neuroinflammation.


Assuntos
Amidoidrolases , Reishi , Triterpenos , Amidoidrolases/antagonistas & inibidores , Carpóforos/química , Humanos , Estrutura Molecular , Reishi/química , Esteroides/análise , Triterpenos/química
5.
Bioorg Chem ; 123: 105759, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35349831

RESUMO

Bislangduoids A and B, a novel class of dimeric diterpenoids based on ent-abietanes tethered by C-17-C-15' bridge, were identified as trace components from a traditional Chinese medicine Euphorbia fischeriana (Langdu). Bislangduoid A features a highly oxidized scaffold incorporating a cage-like pentacyclic core. Their structures were elucidated by extensive spectroscopic techniques, electronic circular dichroism, and NMR calculations. The biosynthetic pathway for the dimeric skeleton and the unique caged moiety via Michael and acetal-formation reactions was proposed. Bislangduoid A showed pronounced cytotoxicity against HepG2 cells through the mitochondria-dependent apoptosis pathway.


Assuntos
Antineoplásicos , Diterpenos , Euphorbia , Abietanos/química , Abietanos/farmacologia , Diterpenos/química , Diterpenos/farmacologia , Euphorbia/química , Estrutura Molecular , Raízes de Plantas/química , Polímeros
6.
Org Biomol Chem ; 20(12): 2508-2517, 2022 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-35266497

RESUMO

Biseuphoids A (1) and B (2), two unprecedented ent-abietane-type diterpenoid dimers linked by monomeric blocks through C-17-C-12' and C-17-C-11', respectively, were isolated from Euphorbia fischeriana, along with their biogenesis related diterpenoid monomers, 17-hydroxyjolkinolide B (3), caudicifolin (4), and fischeriabietane C (5). Their structures were elucidated by extensive spectroscopy assisted by quantum chemical NMR and ECD calculations. The unusual dimeric skeletons are possibly derived from the adduct of diterpenoid monomers through Michael-like reactions. The novel dimers 1 and 2 exhibited inhibitory activities on soluble epoxide hydrolase (sEH) with IC50 values of 8.17 and 5.61 µM, respectively. Molecular dynamics studies illustrated that both 1 and 2 can occupy the catalytic pocket of sEH by forming stable hydrogen bonds with the key amino acid residues including Gln384, Asn378, Pro361, Ala365, Asn366, and Asn472.


Assuntos
Diterpenos , Euphorbia , Abietanos/química , Diterpenos/química , Epóxido Hidrolases/metabolismo , Euphorbia/química , Estrutura Molecular , Raízes de Plantas/química , Polímeros
7.
Front Pharmacol ; 13: 856784, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35295338

RESUMO

CYP3A4-mediated Phase I biotransformation is the rate-limiting step of elimination for many commonly used clinically agents. The modulatory effects of herbal medicines on CYP3A4 activity are one of the risk factors affecting the safe use of drug and herbal medicine. In the present study, the inhibitory effects of nearly hundred kinds of herbal medicines against CYP3A4 were evaluated based on a visual high-throughput screening method. Furthermore, biflavone components including bilobetin (7-demethylginkgetin, DGK), ginkgetin (GK), isoginkgetin (IGK), and amentoflavone (AMF) were identified as the main inhibitory components of Ginkgo biloba L. (GB) and Selaginella tamariscina (P. Beauv.) Spring (ST), which displayed very strong inhibitory effects toward CYP3A4. The inhibitory effects of these biflavones on clinical drugs that mainly undergo CYP3A4-dependent metabolism were evaluated. The IC 50 of GK toward tamoxifen, gefitinib and ticagrelor were found to be of 0.478 ± 0.003, 0.869 ± 0.001, and 1.61 ± 0.039 µM, respectively. These results suggest the potential pharmacokinetic interactions between the identified biflavones and clinical drugs undergoing CYP3A4-mediated biotransformation. The obtained information is important for guiding the rational use of herbal medicine in combination with synthetic pharmaceuticals.

8.
Sci Total Environ ; 822: 153585, 2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35121040

RESUMO

Dimethomorph (DMM), an effective and broad-spectrum fungicide applied in agriculture, is toxic to environments and living organisms due to the hazardous nature of its toxic residues. This study aims to investigate the human cytochrome P450 enzyme (CYP)-mediated oxidative metabolism of DMM by combining experimental and computational approaches. Dimethomorph was metabolized predominantly through a two-step oxidation process mediated by CYPs, and CYP3A was identified as the major contributor to DMM sequential oxidative metabolism. Meanwhile, DMM elicited the mechanism-based inactivation (MBI) of CYP3A in a suicide manner, and the iminium ion and epoxide reactive intermediates generated in DMM metabolism were identified as the culprits of MBI. Furthermore, three common pesticides, prochloraz (PCZ), difenoconazole (DFZ) and chlorothalonil (CTL), could significantly inhibit CYP3A-mediated DMM metabolism, and consequently trigger elevated exposure to DMM in vivo. Computational studies elucidated that the differentiation effects in charge distribution and the interaction pattern played crucial roles in DMM-induced MBI of CYP3A4 during sequential oxidative metabolism. Collectively, this study provided a global view of the two-step metabolic activation process of DMM mediated by CYP3A, which was beneficial for elucidating the environmental fate and toxicological mechanism of DMM in humans from a new perspective.


Assuntos
Citocromo P-450 CYP3A , Morfolinas , Citocromo P-450 CYP3A/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Morfolinas/metabolismo , Oxirredução
9.
Proc Natl Acad Sci U S A ; 119(9)2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35217618

RESUMO

Parkinson's disease (PD) is one of the most common neurodegenerative disorders and is characterized by loss of dopaminergic neurons in the substantia nigra (SN), causing bradykinesia and rest tremors. Although the molecular mechanism of PD is still not fully understood, neuroinflammation has a key role in the damage of dopaminergic neurons. Herein, we found that kurarinone, a unique natural product from Sophora flavescens, alleviated the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits and dopaminergic neurotoxicity, including the losses of neurotransmitters and tyrosine hydroxylase (TH)-positive cells (SN and striatum [STR]). Furthermore, kurarinone attenuated the MPTP-mediated neuroinflammation via suppressing the activation of microglia involved in the nuclear factor kappa B signaling pathway. The proteomics result of the solvent-induced protein precipitation and thermal proteome profiling suggest that the soluble epoxide hydrolase (sEH) enzyme, which is associated with the neuroinflammation of PD, is a promising target of kurarinone. This is supported by the increase of plasma epoxyeicosatrienoic acids (sEH substrates) and the decrease of dihydroxyeicosatrienoic acids (sEH products), and the results of in vitro inhibition kinetics, surface plasmon resonance, and cocrystallization of kurarinone with sEH revealed that this natural compound is an uncompetitive inhibitor. In addition, sEH knockout (KO) attenuated the progression of PD, and sEH KO plus kurarinone did not further reduce the protection of PD in MPTP-induced PD mice. These findings suggest that kurarinone could be a potential natural candidate for the treatment of PD, possibly through sEH inhibition.


Assuntos
Epóxido Hidrolases/metabolismo , Flavonoides/uso terapêutico , Doença de Parkinson/prevenção & controle , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Animais , Modelos Animais de Doenças , Epóxido Hidrolases/genética , Deleção de Genes , Camundongos , Microglia/efeitos dos fármacos , Especificidade por Substrato
10.
Nat Prod Res ; 36(14): 3665-3672, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33538200

RESUMO

Sargentodoxa cuneata (Oliv.) Rehd. et Wils is a traditional Chinese medicine to treat acute appendicitis, rheumarthritis, abdominal pain, and painful menstruation for a long history. The investigation of S. cuneata led to the isolation and identification of twenty-three secondary metabolites, including two new compounds, sargentodoxosides A (1) and B (2), and twenty-one known ones (3-23). Their structural characterization was conducted by HRESIMS, 1 D and 2 D NMR spectra. All the isolated compounds were assayed for their agonistic activities against the farnesoid X receptor (FXR). Nine of the isolated compounds displayed significant agonistic effects against FXR at 0.1 µM, suggesting that they could be served as potential agents for the development of FXR agonists.


Assuntos
Medicina Tradicional Chinesa , Ranunculales , Ranunculales/química
11.
Phytochemistry ; 193: 112974, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34653908

RESUMO

Intestinal commensal fungi are vital to human health, and their metabolites play a key role in the reciprocal relationship. In the present work, eighteen alkaloids and seven monoterpenoids were isolated from the fermentation of the human intestinal fungus Penicillium oxalicum SL2, including seven undescribed alkaloids (penicilloxalines A-G), three undescribed monoterpenoids (penicilloxalines H-J), and fifteen reported compounds. The structures of the isolated compounds were identified by HRESIMS, 1D and 2D NMR, electronic circular dichroism spectra and quantum chemical calculations. Some metabolites displayed moderate agonistic effects against the pregnane X receptor (PXR), whereas (6R)3,7-dimethyl-6,7-dihydroxy-2(Z)-octenoic acid displayed a significant agonistic effect against the farnesoid X receptor (FXR) with an EC50 value of 0.43 µM, which was verified by investigating FXR downstream target genes and proteins, such as small heterodimer partner 1 (SHP1), fibroblast growth factor (FGF), and bile salt export pump (BSEP).


Assuntos
Penicillium , Receptor de Pregnano X , Receptores Citoplasmáticos e Nucleares , Humanos , Intestinos
12.
Phytochemistry ; 193: 113011, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34775270

RESUMO

Metabolites from fungi are a major source of natural small molecule drugs in addition to plants, while fungal derived terpenoids have been confirmed to have great potentials in many diseases. Aspergillus fungi are distributed in every corner of the earth, and their terpenoid metabolites exhibit promising diversity in term of both their chemistry and bioactivity. This review attempted to provide timely and comprehensive coverage of chemical, biosynthesis, and biological studies on terpenoids discovered from the genus Aspergillus, including mono-, sesqui-, di-, sester-, tri-, and meroterpenoids, in the last decade. The structural characteristics, biosynthesis, and pharmacological activities of 288 terpenoids were introduced.


Assuntos
Produtos Biológicos , Terpenos , Aspergillus , Produtos Biológicos/farmacologia , Fungos , Plantas
13.
Environ Pollut ; 293: 118523, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34793912

RESUMO

Carbendazim (CBZ), a broad-spectrum pesticide frequently detected in fruits and vegetables, could trigger potential toxic risks to mammals. To facilitate the assessment of health risks, this study aimed to characterize the cytochrome P450 (CYPs)-mediated metabolism profiles of CBZ by a combined experimental and computational study. Our results demonstrated that CYPs-mediated region-selective hydroxylation was a major metabolism pathway for CBZ in liver microsomes from various species including rat, mouse, minipig, dog, rabbit, guinea pig, monkey, cow and human, and the metabolite was biosynthesized and well-characterized as 6-OH-CBZ. CYP1A displayed a predominant role in the region-selective hydroxylation of CBZ that could attenuate its toxicity through converting it into a less toxic metabolite. Meanwhile, five other common pesticides including chlorpyrifos-methyl, prochloraz, chlorfenapyr, chlorpyrifos, and chlorothalonil could significantly inhibit the region-selective hydroxylation of CBZ, and consequently remarkably increased CBZ exposure in vivo. Furthermore, computational study clarified the important contribution of the key amino acid residues Ser122, and Asp313 in CYP1A1, as well as Asp320 in CYP1A2 to the hydroxylation of CBZ through hydrogen bonds. These results would provide some useful information for the metabolic profiles of CBZ by mammalian CYPs, and shed new insights into CYP1A-mediated metabolic detoxification of CBZ and its health risk assessment.


Assuntos
Sistema Enzimático do Citocromo P-450 , Microssomos Hepáticos , Animais , Benzimidazóis , Carbamatos , Citocromo P-450 CYP1A2/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Hidroxilação , Microssomos Hepáticos/metabolismo , Especificidade da Espécie
14.
Eur J Med Chem ; 224: 113731, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34352712

RESUMO

Intestinal commensal fungi are vital to human health, and their secondary metabolites play a key role in the reciprocal relationship. In the present study, the first example of 2,3-seco ergot alkaloids belonging to clavine-type were isolated from the fermentation of human intestinal fungus Aspergillus fumigatus CY018, including two pairs of diastereoisomers, secofumigaclavines A (3) and B (4) and secofumigaclavines C (5) and D (6), one analogue features a highly unsaturated skeleton, secofumigaclavine E (7), along with two known ones, fumigaclavines C (1) and D (2). Their structures were identified based on extensive spectroscopic data in a combination of quantum chemical calculations. Moreover, a single-step operation of semi-synthetic reaction based on riboflavin (RF)-dependent photocatalysis was performed to obtain the novel 2,3-seco ergot alkaloids 3 and 5 from their biosynthetic precursors 1 and 2. All the isolated compounds were evaluated for their anti-inflammatory activity. Among them, secofumigaclavine B (4) could bind to MD2 with a low micromole level of the equilibrium dissociation constant measured by surface plasmon resonance (SPR), and suppress TLR4-mediated NF-κB signaling pathway in RAW264.7 cells, resulting in its anti-inflammatory effect. Molecular dynamics revealed that amino acid residue Tyr131 played a key role in the interaction of secofumigaclavine B (4) with MD2. These findings suggested that secofumigaclavine B (4) could be considered as a potential candidate for the development of MD2 inhibitors.


Assuntos
Anti-Inflamatórios/uso terapêutico , Aspergillus fumigatus/efeitos dos fármacos , Alcaloides de Claviceps/uso terapêutico , Anti-Inflamatórios/farmacologia , Alcaloides de Claviceps/farmacologia , Humanos
15.
Food Chem Toxicol ; 156: 112516, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34411643

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by dementia. Inhibition of soluble epoxide hydrolase (sEH) regulates inflammation involving in central nervous system (CNS) diseases. However, the exactly mechanism of sEH in AD is still unclear. In this study, we evaluated the vital role of sEH in amyloid beta (Aß)-induced AD mice, and revealed a possible molecular mechanism for inhibition of sEH in the treatment of AD. The results showed that the sEH expression and activity were remarkably increased in the hippocampus of Aß-induced AD mice. Chemical inhibition of sEH by TPPU, a selective sEH inhibitor, alleviated spatial learning and memory deficits, and elevated levels of neurotransmitters in Aß-induced AD mice. Furthermore, inhibition of sEH could ameliorate neuroinflammation, neuronal death, and oxidative stress via stabilizing the in vivo level of epoxyeicosatrienoic acids (EETs), especially 8,9-EET and 14,15-EET, further resulting in the anti-AD effect through the regulation of GSK3ß-mediated NF-κB, p53, and Nrf2 signaling pathways. These findings revealed the underlying mechanism of sEH as a potential therapeutic target in treatment of AD.


Assuntos
Doença de Alzheimer/induzido quimicamente , Peptídeos beta-Amiloides/toxicidade , Eicosanoides/metabolismo , Epóxido Hidrolases/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Animais , Epóxido Hidrolases/genética , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/genética , Transtornos da Memória , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Aprendizagem Espacial/efeitos dos fármacos
16.
Chem Biol Interact ; 345: 109571, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34217688

RESUMO

Soluble epoxide hydrolase (sEH) is a potential drug target to treat inflammation and neurodegenerative diseases. In this study, we found that the extract of Inula britanica exhibited significantly inhibitory effects against sEH, therefore, we investigated its phytochemical constituents to obtain seven new compounds together with sixteen known ones (1-20), including two pairs of novel enantiomers, (2S,3S)-britanicafanin A (1a), (2R,3R)-britanicafanin A (1b), (2R,3S)-britanicafanin B (2a), and (2S,3R)-britanicafanin B (2b), and three new lignans britanicafanins C-E (3-5). Their structures were determined by HRESIMS, 1D and 2D NMR, and electronic circular dichroism (ECD) spectra as well as quantum chemical computations. All the isolates were evaluated for their inhibitory effects against sEH, compounds 1-3, 5-7, 9, 10, 13, 14, and 17-20 showed significant inhibitory effects against sEH with IC50 values from 3.56 µM to 26.93 µM. The inhibition kinetics results indicated that compounds 9, 10, 13, and 19 were all uncompetitive inhibitors, and their inhibition constants (Ki) values were 7.11, 1.99, 4.06, and 8.78 µM, respectively. Their potential interactions were analyzed by molecular docking and molecular dynamics (MD), which suggested that amino acid residues Asp335 and Asn359, especially Gln384, played an important role in the inhibition of compounds 10 and 13 on sEH, and compounds 10 and 13 could be considered as the potential candidates for the development of sEH inhibitors.


Assuntos
Produtos Biológicos/metabolismo , Produtos Biológicos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/metabolismo , Inula/química , Simulação de Dinâmica Molecular , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/química , Cinética , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica , Solubilidade
17.
Int J Biol Macromol ; 183: 811-817, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-33957203

RESUMO

Inhibition of soluble epoxide hydrolase (sEH) is considered to be an effective treatment for inflammation-related diseases, and small molecules origin from natural products show promising activity against sEH. Two undescribed protostanes, 3ß-hydroxy-25-anhydro-alisol F (1) and 3ß-hydroxy-alisol G (2) were isolated from Alisma orientale and identified as new sEH inhibitors with IC50 values of 10.06 and 30.45 µM, respectively. Potential lead compound 1 was determined as an uncompetitive inhibitor against sEH, which had a Ki value of 5.13 µM. In-depth molecular docking and molecular dynamics simulations revealed that amino acid residue Ser374 plays an important role in the inhibition of 1, which also provides an idea for the development of sEH inhibitors based on protostane-type triterpenoids.


Assuntos
Alisma/química , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Triterpenos/farmacologia , Inibidores Enzimáticos/química , Epóxido Hidrolases/química , Concentração Inibidora 50 , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Farmacocinética , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Conformação Proteica , Triterpenos/química
18.
Chem Biol Interact ; 340: 109453, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33785314

RESUMO

Gut bacterial ß-glucuronidase (GUS) plays a pivotal role in the metabolism and reactivation of a vast of glucuronide conjugates of both endogenous and xenobiotic compounds in the gastrointestinal tract of human, which has been implicated in certain drug-induced gastrointestinal tract (GI) toxicity in clinic. Inhibitors of gut microbial GUS exhibited great potentials in relieving the drug-induced GI toxicity. In this study, Selaginella tamariscina and its major biflavonoid amentoflavone (AMF) were evaluated for their inhibitory activity against Escherichia coli GUS. Two selective probe substrates for GUS (a specific fluorescent probe substrate for GUS, DDAOG and a classical drug substrate for GUS, SN38G) were used in parallel for charactering the inhibition behaviors. Both the extract of S. tamariscina and its major biflavonoid AMF displayed evident inhibitory effects on GUS, and the IC50 values of AMF against GUS mediated DDAOG and SN-38G hydrolysis were 0.62 and 0.49 µM, respectively. Inhibition kinetics studies indicated that AMF showed mixed type inhibition for GUS-mediated DDAOG hydrolysis, while displayed competitive type inhibition against GUS-mediated SN-38G hydrolysis, with the Ki values of 0.24 and 1.25 µM, respectively. Molecular docking studies and molecular dynamics stimulation results clarified the role of amino acid residues Leu361, Ile363, and Glu413 in the inhibition of AMF on GUS. These results provided some foundations for the potential clinical utility of S. tamariscina and its major biflavonoid AMF for treating drug-induced enteropathy.


Assuntos
Biflavonoides/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Glucuronidase/antagonistas & inibidores , Selaginellaceae/química , Aminoácidos/metabolismo , Bactérias/efeitos dos fármacos , Bactérias/metabolismo , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Trato Gastrointestinal/microbiologia , Glucuronídeos/metabolismo , Hidrólise/efeitos dos fármacos , Cinética , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular
19.
Biomed Res Int ; 2021: 8010694, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33553430

RESUMO

The gut microbiota is very important in the initiation, progression, and dissemination of cancer, and the regulation of microbiota has been employed as a novel strategy to enhance the effect of immunotherapy. Adiponectin (APN), an adipocyte-derived hormone, plays a vital role in regulating the immune response of innate immune cells. The deficiency of APN inhibits rhabdomyosarcoma growth. However, whether this function is associated with regulating gut microbiota remains unknown. To investigate, we performed 16S ribosomal RNA (rRNA) gene sequencing on the fecal microbiome of APN gene knockout mice to determine whether APN deletion affects the gut microbiota. We found APN deficiency alters gut microbial functions involved in metabolism, genetic information processing, and cellular processes. In addition, a decreased abundance of Bacteroides and an increased abundance of Prevotella and Helicobacter were observed in rhabdomyosarcoma-bearing APN knockout mice; these bacteria were associated with the inhibition of rhabdomyosarcoma growth. These findings suggest that gut microbiota may be a potential target of APN deficiency against rhabdomyosarcoma.


Assuntos
Adiponectina/deficiência , Adiponectina/genética , Microbioma Gastrointestinal/genética , Erros Inatos do Metabolismo/genética , Rabdomiossarcoma/genética , Animais , Bactérias/classificação , Bactérias/genética , Bacteroides/genética , Fezes/microbiologia , Humanos , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/microbiologia , Camundongos , Camundongos Knockout , RNA Ribossômico 16S/genética , Rabdomiossarcoma/complicações , Rabdomiossarcoma/microbiologia
20.
Am J Chin Med ; 49(2): 315-358, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33622212

RESUMO

As a genus of the Asteraceae, Inula is widely distributed all over the world, and several of them are being used in traditional medicines. A number of metabolites were isolated from Inula species, and some of these have shown to possess ranges of pharmacological activities. The genus Inula contains abundant sesquiterpenoids, such as eudesmanes, xanthanes, and sesquiterpenoid dimers and trimers. In addition, other types of terpenoids, flavonoids, and lignins also exist in the genus Inula. Since 2010, more than 300 new secondary metabolites, including several known natural products that were isolated for the first time from the genus Inula. Most of them exhibited potential bioactivities in various diseases. The review aimed to summarize the advance of recent researches (2010-2020) on phytochemical constituents, biosynthesis, and pharmacological properties of the genus Inula for providing a scientific basis and supporting its application and exploitation for new drug development.


Assuntos
Inula/química , Extratos Vegetais , Desenvolvimento de Medicamentos , Humanos , Estrutura Molecular , Extratos Vegetais/biossíntese , Extratos Vegetais/química , Extratos Vegetais/farmacologia
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