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1.
Microb Cell Fact ; 22(1): 51, 2023 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-36918890

RESUMEN

BACKGROUND: ε-Poly-L-lysine (ε-PL) is a natural and safe food preservative that is mainly produced by filamentous and aerobic bacteria Streptomyces albulus. During ε-PL biosynthesis, a large amount of ATP is used for the polymerization of L-lysine. A shortage of intracellular ATP is one of the major factors limiting the increase in ε-PL production. In previous studies, researchers have mainly tried to increase the oxygen supply to enhance intracellular ATP levels to improve ε-PL production, which can be achieved through the use of two-stage dissolved oxygen control, oxygen carriers, heterologous expression of hemoglobin, and supplementation with auxiliary energy substrates. However, the enhancement of the intracellular ATP supply by constructing an ATP regeneration system has not yet been considered. RESULTS: In this study, a polyphosphate kinase (PPK)-mediated ATP regeneration system was developed and introduced into S. albulus to successfully improve ε-PL production. First, polyP:AMP phosphotransferase (PAP) from Acinetobacter johnsonii was selected for catalyzing the conversion of AMP into ADP through an in vivo test. Moreover, three PPKs from different microbes were compared by in vitro and in vivo studies with respect to catalytic activity and polyphosphate (polyP) preference, and PPK2Bcg from Corynebacterium glutamicum was used for catalyzing the conversion of ADP into ATP. As a result, a recombinant strain PL05 carrying coexpressed pap and ppk2Bcg for catalyzing the conversion of AMP into ATP was constructed. ε-PL production of 2.34 g/L was achieved in shake-flask fermentation, which was an increase of 21.24% compared with S. albulus WG608; intracellular ATP was also increased by 71.56%. In addition, we attempted to develop a dynamic ATP regulation route, but the result was not as expected. Finally, the conditions of polyP6 addition were optimized in batch and fed-batch fermentations, and the maximum ε-PL production of strain PL05 in a 5-L fermenter was 59.25 g/L by fed-batch fermentation, which is the highest ε-PL production reported in genetically engineered strains. CONCLUSIONS: In this study, we proposed and developed a PPK-mediated ATP regeneration system in S. albulus for the first time and significantly enhanced ε-PL production. The study provides an efficient approach to improve the production of not only ε-PL but also other ATP-driven metabolites.


Asunto(s)
Adenosina Trifosfato , Polilisina , Fermentación , Regeneración
2.
Adv Sci (Weinh) ; 9(18): e2200670, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35478383

RESUMEN

Natural tissues are composed of ordered architectural organizations of multiple tissue cells. The spatial distribution of cells is crucial for directing cellular behavior and maintaining tissue homeostasis and function. Herein, an artificial bone bioceramic scaffold with star-, Tai Chi-, or interlacing-shaped multicellular patterns is constructed. The "cross-talk" between mesenchymal stem cells (MSCs) and macrophages can be effectively manipulated by altering the spatial distribution of two kinds of cells in the scaffolds, thus achieving controllable modulation of the scaffold-mediated osteo-immune responses. Compared with other multicellular patterns, the Tai Chi pattern with a 2:1 ratio of MSCs to macrophages is more effective in activating anti-inflammatory M2 macrophages, improving MSCs osteogenic differentiation, and accelerating new bone formation in vivo. In brief, the Tai Chi pattern generates a more favorable osteo-immune environment for bone regeneration, exhibiting enhanced immunomodulation and osteogenesis, which may be associated with the activation of BMP-Smad, Oncostatin M (OSM), and Wnt/ß-catenin signaling pathways in MSCs mediated by macrophage-derived paracrine signaling mediators. The study suggests that the manipulation of cell distribution to improve tissue formation is a feasible approach that can offer new insights for the design of tissue-engineered bone substitutes with multicellular interactions.


Asunto(s)
Células Madre Mesenquimatosas , Osteogénesis , Materiales Biocompatibles , Regeneración Ósea , Diferenciación Celular , Osteogénesis/fisiología
3.
Artículo en Inglés | MEDLINE | ID: mdl-34840584

RESUMEN

Cyclophosphamide is a commonly used anticancer drug, and immunosuppression is one of the most common side effects. How to recover the immunological function is important for cyclophosphamide-treated patients. In the present study, Phellodendri Cortex polysaccharides (CPP) could enhance the proliferation of mouse spleen lymphocytes in vitro. The immunoregulatory function of CPP was then investigated in cyclophosphamide-induced immunosuppressed mice. In CPP-treated groups, mice were orally treated with CPP at doses of 1, 0.5, and 0.25 g/kg bodyweight from 1 to 11 d, respectively. The cyclophosphamide was administrated in CPP and cyclophosphamide groups from 12 to 14 d. In the cyclophosphamide and normal control groups, the mice received equal volume of saline from 1 to 14 d. The results showed that CPP (1 g/kg) could significantly increase the bodyweight of mice, even during cyclophosphamide treatment. The organ coefficients of the spleen and thymus were recovered by CPP treatment. CPP upregulated the contents of cytokines (IL-2, IL-6, IFN-γ, and TNF-α) in serum, which were downregulated by cyclophosphamide. The mRNA levels of these cytokines were also elevated by CPP treatment in the spleen. Cyclophosphamide upregulated the expressions of NF-κB p65, TLR4, and MyD88, suggesting that the NF-κB signaling pathway was activated by cyclophosphamide. After CPP treatment, it was recovered to normal level. These results indicated that CPP alleviated the cyclophosphamide-induced immunosuppression.

4.
Front Pharmacol ; 11: 802, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32547398

RESUMEN

Enalaprilat is the active metabolite of enalapril, a widely used antihypertension drug. The human organic anion transporter 3 (OAT3), which is highly expressed in the kidney, plays a critical role in the renal clearance of many drugs. While urinary excretion is the primary elimination route of enalaprilat, direct involvement of OAT3 has not been reported so far. In the present study, OAT3-mediated uptake of enalaprilat was first characterized, and the inhibition of OAT3 transport activity was then examined for a number of flavonoid and drug molecules with diverse structures. A varying degree of inhibition potency was demonstrated for flavonoids, with IC50 values ranging from 0.03 to 22.6 µM against OAT3 transport activity. In addition, commonly used drugs such as urate transporter 1 (URAT1) inhibitors also displayed potent inhibition on OAT3-mediated enalaprilat uptake. Pharmacophore and three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses revealed the presence of a polar center and a hydrophobic region involved in OAT3-inhibitor binding. For the polar center, hydroxyl groups present in flavonoids could act as either hydrogen bond donors or acceptors and the number and position of hydroxyl groups were critical drivers for inhibition potency, while carboxyl groups present in some drugs could form ionic bridges with OAT3. The predicted inhibition potencies by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were correlated well with experimental IC50 values. Taken together, the present study identified OAT3-mediated uptake of enalaprilat as an important mechanism for its renal clearance, which may be liable for drug-drug and herb-drug interactions. The established computational models revealed unique structural features for OAT3 inhibitors and could be used for structure-activity relationship (SAR) analysis of OAT3 inhibition. The clinical relevance of the inhibition of OAT3-mediated enalaprilat uptake warrants further investigation, particularly in populations where herbal remedies and drugs are used concomitantly.

5.
Fitoterapia ; 143: 104562, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32199960

RESUMEN

A new cyclopeptide, pulvpeptin A (1), two pairs of norlignan lignanosides, tamariscinosides G and H (2, 3), together with five known compounds (4-8) were isolated from Selaginella pulvinata. The structures were elucidated by spectroscopic data and chemical degradation. The activity of tamariscinoside G (2) was evaluated by stimulating glucose uptake in 3T3-L1 adipocytes. The results showed 1.49-fold increase in glucose uptake in 3T3-L1 cells relative to basal.


Asunto(s)
Lignanos/farmacología , Péptidos Cíclicos/farmacología , Selaginellaceae/química , Células 3T3-L1 , Animales , China , Glucosa/metabolismo , Lignanos/aislamiento & purificación , Ratones , Estructura Molecular , Péptidos Cíclicos/aislamiento & purificación , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología
6.
J AOAC Int ; 103(2): 504-512, 2020 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-31561752

RESUMEN

BACKGROUND: Peucedani Radix is a popular traditional Chinese medicine herb with a long history in China. Praeruptorin A (PA), praeruptorin B (PB), and praeruptorin E (PE) are usually taken as important quality indexes of Peucedani Radix. OBJECTIVE: To establish a rapid method for simultaneous determination of PA, PB, PE, and moisture contents in Peucedani Radix using near-infrared (NIR) spectroscopy and chemometrics. METHODS: One hundred twenty Peucedani Radix samples were analyzed with HPLC as a reference method. The NIR spectral scanning range was from 12000 cm-1 to 4000 cm-1. Partial least squares (PLS) regression algorithm was used to establish calibration models. Three variable selection methods were investigated, including variable importance in projection (VIP), competitive adaptive reweighted sampling (CARS), and Monte Carlo uninformative variable elimination (MCUVE). The performances of the established models were evaluated by root-mean-square error (RMSEC) and determination coefficient (Rc2) of calibration set, root-mean-square error (RMSEP) and determination coefficient (Rp2) of prediction set, and residual predictive deviation (RPD). RESULTS: A clear ranking of the performance of the calibration models could be as follows: CARS-PLS > MCUVE-PLS > VIP-PLS > Full-PLS. For CARS-PLS, Rp2, RMSEP, and RPD of the prediction set are as follows: 0.9204, 0.0860%, and 3.5850 for PA; 0.8011, 0.0431%, and 2.0868 for PB; 0.8043, 0.0367%, and 2.1569 for PE; and 0.9249, 0.3350%, and 3.6551 for moisture, respectively. CONCLUSIONS: The NIR spectroscopy combined with CARS-PLS calibration models could be used for rapid and accurate determination of PA, PB, PE, and moisture contents in Peucedani Radix samples.


Asunto(s)
Espectroscopía Infrarroja Corta , China , Cumarinas
7.
Chem Biol Interact ; 310: 108745, 2019 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-31299240

RESUMEN

Ursodeoxycholic acid (UDCA) is a major effective constituent of bear bile powder, which is widely used as function food in China and is documented in the Chinese pharmacopoeia as a traditional Chinese medicine. UDCA has been developed as the only accepted therapy by the US FDA for primary biliary cholangitis. Recently, the US FDA granted accelerated approval to obeticholic acid (OCA), a semisynthetic bile acid derivative from chenodeoxycholic acid, for primary biliary cholangitis. However, some perplexing toxicities of UDCA have been reported in the clinic. The present work aimed to investigate the difference between UDCA and OCA in regard to potential metabolic activation through acyl glucuronidation and hepatic accumulation of consequent acyl glucuronides. Our results demonstrated that the metabolic fates of UDCA and OCA were similar. Both UDCA and OCA were predominantly metabolically activated by conjugation to the acyl glucuronide in human liver microsomes. UGT1A3 played a predominant role in the carboxyl glucuronidation of both UDCA and OCA, while UGT2B7 played a major role in their hydroxyl glucuronidation. Further uptake studies revealed that OATP1B1- and 1B3-transfected cells could selectively uptake UDCA acyl glucuronide, but not UDCA, OCA, and OCA acyl glucuronide. In summary, the liver disposition of OCA is different from that of UDCA due to hepatic uptake, and liver accumulation of UDCA acyl glucuronide might be related to the perplexing toxicities of UDCA.


Asunto(s)
Ácido Quenodesoxicólico/análogos & derivados , Glucurónidos/metabolismo , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Microsomas Hepáticos/metabolismo , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/metabolismo , Ácido Ursodesoxicólico/metabolismo , Animales , Transporte Biológico , Ácido Quenodesoxicólico/metabolismo , Humanos , Medicina Tradicional China , Ursidae , Ácido Ursodesoxicólico/análogos & derivados , Ácido Ursodesoxicólico/toxicidad
8.
J Agric Food Chem ; 67(32): 9079-9087, 2019 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-31353905

RESUMEN

Organic anion transporting polypeptides (OATPs) 1B1 and 1B3 are two highly homologous transporters expressed in the human liver. However, epigallocatechin gallate (EGCG), which is the most predominant catechin in green tea, has opposite effects on the function of OATP1B1 and OATP1B3. In the present study, the critical structural domains and amino acid residues for the activation of OATP1B3 by EGCG have been determined by characterizing the function of a series of OATP1B3-derived chimeric transporters, site-directed mutagenesis, and kinetic studies. Our results showed that G45 and F555 in transmembrane domains 1 and 10 are the most important amino acid residues for OATP1B3 activation. Kinetic studies showed that the activation of OATP1B3 by EGCG at a low substrate concentration was due to its increased substrate binding affinity. However, EGCG caused increased Km and decreased Vmax for 1B3-G45A and 1B3-F555H. The flexibility at position 45 and aromaticity at position 555 might be important for OATP1B3 activation. While 1B3-G45A and 1B3-F555H could not be activated by EGCG, their transport activity for EGCG was comparable to that of wild-type OATP1B3. In conclusion, the present study elucidated the molecular mechanism for OATP1B3 activation by EGCG.


Asunto(s)
Catequina/análogos & derivados , Extractos Vegetales/metabolismo , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/química , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/metabolismo , Secuencias de Aminoácidos , Camellia sinensis/química , Catequina/química , Catequina/metabolismo , Células HEK293 , Humanos , Cinética , Hígado/metabolismo , Transportador 1 de Anión Orgánico Específico del Hígado/química , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Modelos Moleculares , Extractos Vegetales/química , Dominios Proteicos , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/genética
9.
Fitoterapia ; 137: 104190, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31163199

RESUMEN

The genus Tripterygium belongs to the family Celastraceae, and contains three species, i.e. Tripterygium wilfordii Hook. F, Tripterygium hypoglaucum (Levl.) Hutch. and Tripterygium regelii Sprague et Takeda. All three species are reported to have excellent medicinal properties that help to cure rheumatoid arthritis, nephrotic syndrome, systemic lupus erythematosus and widely used as a folk medicine in China. Phytochemical studies have led to discovering more than 500 secondary metabolites in this genus, including five main types: sesquiterpenoids, diterpenes, triterpenoids, flavonoids, lignans. This work provides structurally grouping statistic of 198 secondary metabolites of Tripterygium species published from 2008 to the present, as well as pharmacological knowledges in the past five years. The information will be helpful for developing the new discoveries of medicinal value related to the genus Tripterygium.


Asunto(s)
Tripterygium/química , Tripterygium/clasificación , Animales , Antiinflamatorios/química , Antineoplásicos Fitogénicos/química , Antioxidantes/química , Antivirales/química , Diterpenos/química , Flavonoides/química , Humanos , Inmunosupresores/química , Lignanos/química , Estructura Molecular , Fármacos Neuroprotectores/química , Fitoquímicos/química , Metabolismo Secundario , Sesquiterpenos/química , Triterpenos/química
10.
Chin Med ; 13: 53, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30386416

RESUMEN

BACKGROUND: Major depressive disorder (MDD) is a highly heterogeneous disease. Further classification may characterize its heterogeneity. The purpose of this study was to examine whether metabolomic variables could differentiate traditional Chinese medicine (TCM) diagnostic subtypes of MDD. METHODS: Fifty medication-free patients who were experiencing a recurrent depressive episode were classified into Liver Qi Stagnation (LQS, n = 30) and Heart and Spleen Deficiency (HSD, n = 20) subtypes according to TCM diagnosis. Healthy volunteers (n = 28) were included as controls. Gas chromatography-mass spectrometry (GC-MS) was used to examine serum and urinary metabolomic profiles. RESULTS: Twenty-eight metabolites were identified for good separations between TCM subtypes and healthy controls in serum samples. Both TCM subtypes had similar profiles in proteinogenic branched-chain amino acids (BCAAs) (valine, leucine, and isoleucine) and energy metabolism-related metabolites that were differentiated from healthy controls. The LQS subtype additionally differed from healthy controls in multiple amino acid metabolites that are involved in biosynthesis of monoamine and amino acid neurotransmitters, including phenylalanine, 3-hydroxybutric acid, o-tyrosine, glycine, l-tryptophan, and N-acetyl-l-aspartic acid. Threonic acid, methionine, stearic acid, and isobutyric acid are differentially associated with the two subtypes. CONCLUSIONS: While both TCM subtypes are associated with aberrant BCAA and energy metabolism, the LQS subtype may represent an MDD subpopulation characterized by abnormalities in the biosynthesis of monoamine and amino acid neurotransmitters and closer associations with stress-related pathophysiology. The metabolites differentially associated with the two subtypes are promising biomarkers for predicting TCM subtype-specific antidepressant response [registered at http://www.clinicaltrials.gov (NCT02346682) on January 27, 2015].

11.
Phytomedicine ; 41: 54-61, 2018 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-29519319

RESUMEN

BACKGROUND: Gnaphalium affine D. Don is a folk medicine of China believed to be efficacious in the treatment of many ailments, including hyperuricemia and gout. PURPOSE: Based on a previous study, we isolated two flavones, luteolin and luteolin-4'-O-glucoside, from G. affine. Our aim was to assess the potential beneficial effects of treatment and mechanisms of these two flavones on hyperuricemia and acute gouty arthritis. METHODS: The model of potassium oxonate (PO)-induced hyperuricemia and monosodium urate (MSU) crystal-induced inflammation in mice has been established. We evaluated serum uric acid (Sur), xanthine oxidase (XO) activity, protein expression of urate transporter 1 (mURAT1) and glucose transporter 9 (mGLUT9) in renal and kidney protection in a hyperuricemia model. In addition, paw swelling and levels of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in serum were assessed in MSU crystal-induced mice. RESULTS: Luteolin and luteolin-4'-O-glucoside showed a potent clinical effect in treating hyperuricemia and gout. We observed that the two flavones possess potent effect in hyperuricemia mice by decreasing the level of mURAT1 and inhibiting XO activity, which contribute to enhancing uric acid (UA) excretion and improving hyperuricemia-induced renal dysfunction. In addition, luteolin and luteolin-4'-O-glucoside also alleviated paw swelling and inflammation induced by MSU crystals. Further investigation implied that luteolin and luteolin-4'-O-glucoside improved the symptoms of inflammation by decreasing the levels of IL-1ß and TNF-α. CONCLUSION: The present study suggests that luteolin and luteolin-4'-O-glucoside could be developed as therapeutics for treating hyperuricemia and gouty arthritis.


Asunto(s)
Artritis Gotosa/tratamiento farmacológico , Glucósidos/farmacología , Gnaphalium/química , Hiperuricemia/tratamiento farmacológico , Luteolina/farmacología , Animales , Artritis Gotosa/inducido químicamente , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/química , Edema/tratamiento farmacológico , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Hiperuricemia/metabolismo , Interleucina-1beta/metabolismo , Riñón/metabolismo , Masculino , Ratones Endogámicos ICR , Transportadores de Anión Orgánico/metabolismo , Ácido Úrico/sangre , Ácido Úrico/toxicidad , Xantina Oxidasa/metabolismo
12.
Chem Biol Interact ; 277: 79-84, 2017 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-28890383

RESUMEN

Rhein, a major bioactive compound of many medicinal herbs and the prodrug of diacerein, is often used with low dose of methotrexate as drug combination to treat rheumatoid arthritis. In this study, potential drug-drug interaction between methotrexate and rhein was investigated based on organic anion transporters (OAT). Our study demonstrated that rhein acyl glucuronide (RAG), the major metabolite of rhein in the human blood circulation, significantly inhibited the uptake of p-aminohippurate in hOAT1 transfected cells with IC50 value of 691 nM and estrone sulfate uptake in hOAT3 transfected cells with IC50 value of 78.5 nM. As the substrate of both hOAT1 and hOAT3, the methotrexate transport was significantly inhibited by RAG in hOAT1 transfected cells at 50 µM and hOAT3 transfected cells at 1 µM by 69% and 87%, respectively. Further in vivo study showed that after co-administrated with RAG in rats the AUC0-24 values of methotrexate increased from 3109 to 5370 ng/mL*hr and the t1/2 was prolonged by 40.5% (from 7.4 to 10.4 h), demonstrating the inhibitory effect of RAG on methotrexate excretion. In conclusion, rhein acyl glucuronide could significantly decrease the transport of methotrexate by both hOAT1 and hOAT3. The combination use of rhein, diacerein or other rhein-containing herbs with methotrexate may cause obvious drug-drug interaction and require close monitoring for potential drug interaction in clinical practice.


Asunto(s)
Antraquinonas/farmacología , Antirreumáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Glucurónidos/farmacología , Metotrexato/farmacocinética , Transportadores de Anión Orgánico/antagonistas & inhibidores , Animales , Antraquinonas/metabolismo , Interacciones Farmacológicas , Inhibidores Enzimáticos/metabolismo , Glucurónidos/metabolismo , Células HEK293 , Humanos , Masculino , Proteína 1 de Transporte de Anión Orgánico/antagonistas & inhibidores , Proteína 1 de Transporte de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico Sodio-Independiente/antagonistas & inhibidores , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Ratas Sprague-Dawley
13.
BMC Complement Altern Med ; 17(1): 320, 2017 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-28623927

RESUMEN

BACKGROUND: The Gnaphalium pensylvanicum willd. is used in China as a folk medicine to treat anti-inflammatory, cough and rheumatism arthritis. The aim of this study was to evaluate the potential of the extract of G. pensylvanicum to treat hyperuricemia and acute gouty arthritis in animal model. METHODS: G. pensylvanicum extract was evaluated in an experimental model with potassium oxonate (PO) induced hyperuricemia in mice which was used to evaluate anti-hyperuricemia activity and xanthine oxidase (XO) inhibition. Therapies for acute gouty arthritis was also investigated on monosodium urate (MSU) crystal induced paw edema model. RESULTS: G. pensylvanicum extract showed activity in reducing serum uric acid (Sur) through effect renal glucose transporter 9 (GLUT9), organic anion transporter 1 (OAT1) and urate transporter 1 (URAT1) mainly and inhibited XO activity in vivo of mice with PO induced hyperuricemia. The extract of G. pensylvanicum also showed significant anti-inflammatory activity and reduced the paw swelling on MSU crystal-induced paw edema model. Meanwhile, 13 caffeoylquinic acid derivatives and 1 flavone were identified by UPLC-ESI-MS/MS as the main active component of G. pensylvanicum. CONCLUSIONS: The extract of G. pensylvanicum showed significant effect on evaluated models and therefore may be active agents for the treatment of hyperuricemia and acute gouty arthritis.


Asunto(s)
Antiinflamatorios/administración & dosificación , Artritis Gotosa/tratamiento farmacológico , Gnaphalium/química , Supresores de la Gota/administración & dosificación , Hiperuricemia/tratamiento farmacológico , Extractos Vegetales/administración & dosificación , Ácido Quínico/análogos & derivados , Animales , Antiinflamatorios/química , Artritis Gotosa/inmunología , Modelos Animales de Enfermedad , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Supresores de la Gota/química , Humanos , Hiperuricemia/genética , Hiperuricemia/inmunología , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Ratones , Fitoterapia , Extractos Vegetales/química , Ácido Quínico/administración & dosificación , Ácido Quínico/química , Ácido Úrico/metabolismo
14.
J Ethnopharmacol ; 203: 304-311, 2017 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-28390941

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: The Gnaphalium affine D. Don is used in China as a folk medicine to treat gout, anti-inflammatory, antitussive and expectorant activities. The aim of this study was to evaluate the potential of the extract of G. affine to treat hyperuricemia and acute gouty arthritis in animal model. MATERIALS AND METHODS: G. affine extract was evaluated in an experimental model with potassium oxonate (PO) induced hyperuricemia in mice which was used to evaluate anti-hyperuricemia activity and xanthine oxidase (XO) inhibition. Therapies for acute gouty arthritis was also investigated on monosodium urate (MSU) crystal induced paw edema model. RESULTS: G. affine extract showed expressive results on active in reducing serum uric acid (Sur) through effect renal mGLUT9 and mURAT1 mainly and inhibit XO activity in vivo. The extract of G. affine also showed significant anti-inflammatory activity and reduced the paw swelling on MSU crystal-induced paw edema model. Meanwhile, eight major compounds were identified by HPLC-ESI-QTOF-MS/MS. CONCLUSIONS: The extract of G. affine showed significant effect on evaluated models and therefore may be active agents for the treatment of hyperuricemia and acute gouty arthritis.


Asunto(s)
Artritis Gotosa/tratamiento farmacológico , Gnaphalium/química , Hiperuricemia/tratamiento farmacológico , Extractos Vegetales/farmacología , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/farmacología , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Edema/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos ICR , Ácido Oxónico/toxicidad , Espectrometría de Masas en Tándem , Ácido Úrico/sangre , Xantina Oxidasa/antagonistas & inhibidores
15.
Molecules ; 21(9)2016 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-27649136

RESUMEN

In this study, a new method based on immobilized metal affinity chromatography (IMAC) combined with ultrafiltration-ultra performance liquid chromatography-mass spectrometry (UF-UPLC-MS) was developed for discovering ligands for xanthine oxidase (XO) in Gnaphalium hypoleucum DC., a folk medicine used in China for the treatment of gout. By IMAC, the high flavonoid content of G. hypoleucum could be determined rapidly and efficiently. UF-UPLC-MS was used to select the bound xanthine oxidase ligands in the mixture and identify them. Finally, two flavonoids, luteolin-4'-O-glucoside and luteolin, were successfully screened and identified as the candidate XO inhibitors of G. hypoleucum. They were evaluated in vitro for XO inhibitory activity and their interaction mechanism was studied coupled with molecular simulations. The results were in favor of the hypothesis that the flavonoids of G. hypoleucum might be the active content for gout treatment by inhibiting XO.


Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Flavonoides/química , Flavonoides/aislamiento & purificación , Gnaphalium/química , Xantina Oxidasa/antagonistas & inhibidores , Animales , Bovinos , Cromatografía de Afinidad , Cromatografía Líquida de Alta Presión , Espectrometría de Masas , Ultrafiltración , Xantina Oxidasa/química
16.
ACS Chem Neurosci ; 7(11): 1575-1584, 2016 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-27569066

RESUMEN

Adenosine receptor A2A antagonists have emerged as potential treatment for Parkinson's disease in the past decade. We have recently reported a series of adenosine receptor antagonists using heterocycles as bioisosteres for a potentially unstable acetamide. These compounds, while showing excellent potency and ligand efficiency, suffered from moderate cytochrome P450 inhibition and high clearance. Here we report a new series of adenosine receptor A2A antagonists based on a 4-amino-5-carbonitrile pyrimidine template. Compounds from this new template exhibit excellent potency and ligand efficiency with low cytochrome P450 inhibition. Although the clearance remains moderate to high, the leading compound, when dosed orally as low as 3 mg/kg, demonstrated excellent efficacy in the haloperidol induced catalepsy rat model for Parkinson's disease.


Asunto(s)
Antagonistas del Receptor de Adenosina A2/farmacología , Antiparkinsonianos/farmacología , Pirimidinas/farmacología , Antagonistas del Receptor de Adenosina A2/síntesis química , Antagonistas del Receptor de Adenosina A2/farmacocinética , Animales , Antiparkinsonianos/síntesis química , Antiparkinsonianos/farmacocinética , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Haloperidol , Humanos , Ratones , Microsomas Hepáticos/efectos de los fármacos , Simulación del Acoplamiento Molecular , Estructura Molecular , Trastornos Parkinsonianos/tratamiento farmacológico , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas , Relación Estructura-Actividad
17.
J Agric Food Chem ; 64(28): 5742-50, 2016 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-27362917

RESUMEN

Rhein is a major component of the many medicinal herbs such as rhubarb. Despite wide use, intoxication cases associated with rhein-containing herbs are often reported. The present work aimed to investigate if rhein was subject to metabolic activation leading to toxicity. Upon incubations with different species of liver microsomes, three monoglucuronides were identified, corresponding to two hydroxyl glucuronides and one acyl glucuronide via the carboxyl group, respectively. Further study revealed that rhein acyl glucuronide was chemically reactive, and showed cytotoxicity toward hepatocarcinoma cells. In addition, significant species differences in glucuronidation of rhein were observed between laboratory animals and humans. Reaction phenotyping experiments demonstrated that rhein acyl glucuronide was catalyzed predominantly by uridine 5'-diphospho-glucuronosyltransferase 1A1, 1A9, and 2B7. Taken together, the present study confirmed that rhein could be metabolically activated via the formation of acyl glucuronide, especially in human.


Asunto(s)
Antraquinonas/metabolismo , Medicamentos Herbarios Chinos/metabolismo , Extractos Vegetales/metabolismo , Rheum/química , Activación Metabólica , Animales , Antraquinonas/química , Antraquinonas/toxicidad , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/toxicidad , Glucuronosiltransferasa/metabolismo , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Extractos Vegetales/toxicidad
18.
Pharm Biol ; 54(2): 293-302, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-25858254

RESUMEN

CONTEXT: Organic anion-transporting polypeptide 2B1 (OATP2B1) which is highly expressed in enterocytes and hepatocytes could be a key determinant for the intestinal absorption and hepatic uptake of its substrate drugs. Natural products are commonly used in traditional Chinese medicine, foods, and beverages. OBJECTIVE: The objective of this study is to determine the OATP2B1-mediated drug interactions that could occur between natural products and OATP2B1 substrate drugs. MATERIALS AND METHODS: Human OATP2B1 was transiently expressed in human embryonic kidney (HEK293) cells and characterized by immunofluorescence, Western blot, and uptake assay. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods for detecting OATP2B1 substrates estrone-3-sulfate (E3S) and three statins had been developed and were employed to investigate the effects of 27 frequently used natural products on the function of OATP2B1. Uptake of 5 µM E3S and 1 µM statins in the absence or presence of natural products was measured at 37 °C for 2 min with empty vector- and OATP2B1-transfected HEK293 cells. The IC50 values of inhibitors for OATP2B1-mediated 5 µM E3S uptake were determined. RESULTS: Our results showed that mulberrin, scutellarin, quercetin, and glycyrrhetinic acid were strong inhibitors of OATP2B1-mediate E3S uptake with IC50 values being 1.8, 2.0, 7.5, and 13.0 µM, which were comparable with their plasma concentrations in clinical trials. They also inhibited OATP-mediated uptake of atorvastatin, fluvastatin, and rosuvastatin. These results indicated that clinically relevant drug interactions could occur between these natural compounds and OATP2B1 substrate drugs. DISCUSSION AND CONCLUSION: The information obtained from this study might be helpful to predict and to avoid potential OATP2B1-mediated drug interactions.


Asunto(s)
Productos Biológicos/farmacología , Medicamentos Herbarios Chinos/farmacología , Estrona/análogos & derivados , Inhibidores de Hidroximetilglutaril-CoA Reductasas/metabolismo , Transportadores de Anión Orgánico/antagonistas & inhibidores , Western Blotting , Cromatografía Liquida , Estrona/metabolismo , Técnica del Anticuerpo Fluorescente , Células HEK293 , Interacciones de Hierba-Droga , Humanos , Transportadores de Anión Orgánico/genética , Transportadores de Anión Orgánico/metabolismo , Especificidad por Sustrato , Espectrometría de Masas en Tándem , Transfección
19.
Molecules ; 20(12): 22220-35, 2015 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-26690404

RESUMEN

Rhizoma Atractylodes macrocephala polysaccharides (RAMP) have been reported to have a variety of important biological activities. In this study, an ultrasonic-assisted enzymatic extraction (UAEE) was employed to obtain the highest extraction yield and strongest antioxidant activity of RAMP and optimized by a multi-response optimization process. A three-level four-factor Box-Behnken design (BBD) was performed as response surface methodology (RSM) with desirability function (DF) to attain the optimal extraction parameters. The DPPH scavenging percentage was used to represent the antioxidant ability of RAMP. The maximum D value (0.328), along with the maximum yield (59.92%) and DPPH scavenging percentage (13.28%) were achieved at 90.54 min, 57.99 °C, 1.95% cellulase and 225.29 W. These values were further validated and found to be in good agreement with the predicted values. Compared to the other extraction methods, both the yield and scavenging percentage of RAMP obtained by UAEE was favorable and the method appeared to be time-saving and of high efficiency. These results demostrated that UAEE is an appropriate and effective extraction technique. Moreover, RSM with DF approach has been proved to be adequate for the design and optimization of the extraction parameters for RAMP. This work has a wide range of implications for the design and operation of polysaccharide extraction processes.


Asunto(s)
Antioxidantes/química , Asteraceae/química , Extracción Líquido-Líquido/métodos , Extractos Vegetales/química , Polisacáridos/química , Antioxidantes/aislamiento & purificación , Compuestos de Bifenilo/antagonistas & inhibidores , Celulasa/química , Análisis Factorial , Picratos/antagonistas & inhibidores , Polisacáridos/aislamiento & purificación , Sonicación
20.
J Med Chem ; 58(19): 7775-84, 2015 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-26359680

RESUMEN

In search for prodrugs to address the issue of pH-dependent solubility and exposure associated with 1 (BMS-582949), a previously disclosed phase II clinical p38α MAP kinase inhibitor, a structurally novel clinical prodrug, 2 (BMS-751324), featuring a carbamoylmethylene linked promoiety containing hydroxyphenyl acetic acid (HPA) derived ester and phosphate functionalities, was identified. Prodrug 2 was not only stable but also water-soluble under both acidic and neutral conditions. It was effectively bioconverted into parent drug 1 in vivo by alkaline phosphatase and esterase in a stepwise manner, providing higher exposure of 1 compared to its direct administration, especially within higher dose ranges. In a rat LPS-induced TNFα pharmacodynamic model and a rat adjuvant arthritis model, 2 demonstrated similar efficacy to 1. Most importantly, it was shown in clinical studies that prodrug 2 was indeed effective in addressing the pH-dependent absorption issue associated with 1.


Asunto(s)
Organofosfatos/farmacología , Fenilacetatos/farmacología , Profármacos/química , Profármacos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Administración Oral , Animales , Artritis Experimental/tratamiento farmacológico , Disponibilidad Biológica , Técnicas de Química Sintética , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Macaca fascicularis , Masculino , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Estructura Molecular , Organofosfatos/química , Fenilacetatos/química , Profármacos/farmacocinética , Inhibidores de Proteínas Quinasas/química , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Solubilidad , Relación Estructura-Actividad
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