Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 21
Filtrar
1.
ACS Appl Mater Interfaces ; 13(38): 45315-45324, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34520665

RESUMO

Active targeted therapy for bowel cancer using untethered microrobots has attracted extensive attention. However, traditional microrobots face challenges, such as issues of mobility, biocompatibility, drug loading, sustained-release capabilities, and targeting accuracy. Here, we propose an untethered triple-configurational magnetic robot (TCMR) that is composed of three geometrically nested parts: actuation and guarding, anchoring and seeding, and drug release part. A targeting magnetic driving system actuates the TCMR along the predetermined trajectory to the target position. The pH-sensitive actuation and guarding part formed by electrodeposition is degraded in the intestinal environment and separates from the two other parts. A majority of magnetic nanoparticles encapsulated in this part are retrieved. The anchoring and seeding part anchors the lesion area and seeds the drug release part in the gaps of intestinal villi by hydrolysis. Ultimately, the drug release part containing the therapeutic completes the sustained release to prolong the duration of the therapeutic agent. Cytotoxicity and therapeutic tests reveal that TCMRs are biocompatible and suitable for targeted therapy and have good therapeutic performance. The newly designed TCMR will provide new ideas for targeted therapy, thus expanding the application scope of robotics technology in the biomedical field.

2.
Reprod Toxicol ; 105: 156-165, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34481919

RESUMO

We and others have previously shown that abnormal pelvic environment plays an important role in the unexplained infertility of endometriosis. However, whether iron overload caused by ectopic periodic bleeding found in patients with endometriosis participates in endometriosis-associated reproductive failure is unknown. This study aimed to investigate effects of iron at level relevant to pelvic iron overload on the development of preimplantation mouse embryo. Two-cell embryos were collected, and cultured to blastocysts in G1/G2 medium supplemented with iron alone or in combination with iron chelator. The development rates, ATP level, mitochondrial membrane potential (MMP), reactive oxygen species level (ROS), and apoptotic and ferroptotic indices were compared between control and iron treatments across each specific developmental stage. Prolonged exposure to iron remarkably impaired early embryo development in vitro by hampering blastocyst formation (P < 0.001), which could be partly restored by iron chelator (P < 0.001). The arrest of embryo development was linked with iron-initiated mitochondrial dysfunction with reduction of ATP generation and MMP (P < 0.05 and P < 0.001, respectively). Impaired mitochondria altered ROS accumulation post-iron exposure at morula stage and blastocyst stage (P < 0.05). Moreover, Iron-exposed blastocyst stage embryos showed higher apoptotic and ferroptotic rates (P < 0.001 and P < 0.05, respectively). Our results highlight that pathologically relevant level of iron compromises preimplantation mouse embryo development by disrupting mitochondrial function and triggering both apoptosis and ferroptosis, which implicates that excess iron found in peritoneal fluid of women with endometriosis likely participates in endometriosis-associated reproductive failure.

3.
J Ovarian Res ; 14(1): 94, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34261510

RESUMO

BACKGROUND: Laser-assisted hatching (LAH) has been widely applied to facilitate blastocyst hatching in IVF-ET treatment, however, the effect of LAH on subsequent development and clinical outcomes of the lower grade cleavage stage embryos (LGCE) remains unknown. Our study aimed at evaluating the effect of LAH on blastocyst formation and the clinical pregnancy outcomes of LGCE embryos after transfer. METHODS: A total of 608 cycles of IVF/ICSI treatment from November 2017 to September 2019 were included in our study as follows: 296 in the LAH group and 312 in the N-LAH group. The total blastocyst rate, usable blastocyst rate, good-grade blastocyst rate and clinical pregnancy rate were statistically compared between the two groups. RESULTS: The total blastocyst rate (50.7% vs 40.2%, P < 0.001), usable blastocyst rate (31.0% vs 18.6%, P < 0.001) were significantly higher in the LAH group than those in the N-LAH group. After analysis of generalized estimating equations, LAH was positively correlated with the blastocyst rate (B = 0.201, OR 95% CI = 1.074-1.393, P = 0.002), usable blastocyst rate (B = 0.478, OR 95% CI = 1.331-1.955, P < 0.001). However, the clinical pregnancy rate after blastocyst transfer did not differ between LAH group and N-LAH group (49.4% vs 40.0%, P > 0.05, respectively). CONCLUSIONS: A higher proportion of total blastocysts and usable blastocysts can be obtained by LAH in LGCE, which may be beneficial to the outcome of the IVF/ICSI-ET cycle.

4.
Appl Opt ; 59(25): 7638-7645, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32902464

RESUMO

Laser-induced breakdown plasma was used for gas temperature measurement based on the residual energy of a laser pulse defined as the laser energy detected in the beam path as well as plasma emissions. Gas mixtures with different compositions (O2/N2, O2/CO2, and O2/N2/CO2) were used to simulate the main components of combustion products at different temperatures. First, the correlation of residual energy and gas temperature was investigated, which showed that the residual energy increased with an increase in the gas temperature. The results showed that it also relates to the gas composition, which would affect the characteristics of laser-induced plasma. Then the spectral emission ratio of the plasma (O/N, O/C, and C/N) was obtained simultaneously to correct the compositional effect on the temperature measurement. Finally, the gas temperature with different components can be obtained by the equation coupled with the gas temperature, residual energy, and gas composition. The corrected temperature is consistent with that obtained by thermocouple and the gas temperature measurement error is less than 3.5% in the range from 309 K to 548 K.

5.
J Pharm Pharmacol ; 72(12): 1771-1786, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32648321

RESUMO

OBJECTIVES: Bavachin is a bioactive natural flavonoid with oestrogen-like activity. Here, we aimed to investigate its metabolic and disposal fates involving in CYPs, UGTs and efflux transporters. METHODS: Phase I metabolism and glucuronidation were performed by human liver microsomes (HLM). Reaction phenotyping and activity correlation analysis were performed to identify the main CYP and UGT isozymes. Chemical inhibition and gene knock-down approaches were employed to explore the function of BCRP and MRPs. KEY FINDINGS: Five phase I metabolites (M1-M5) and three glucuronides (G1-G3) were identified. The CLint values for M4 and G1 by HLM were 127.99 and 1159.07 µl/min per mg, respectively. Reaction phenotyping results suggested CYP1A1 (208.85 µl/min per mg) and CYP2C9 (107.51 µl/min per mg), and UGT1A1 (697.19 µl/min per mg), UGT1A7 (535.78 µl/min per mg), UGT1A8 (247.72 µl/min per mg) and UGT1A9 (783.68 µl/min per mg) all participated in the metabolism of bavachin. In addition, activity correlation analysis also supported the results above. Furthermore, the metabolism exhibited marked species differences, and rabbits were the appropriate model animals. Moreover, MRP4 was identified as the main contributor based on chemical inhibition and gene silencing approaches. CONCLUSIONS: CYP1A1 and CYP2C9, UGT1A1, UGT1A7, UGT1A8 and UGT1A9, and MRP4 all played important roles in the metabolism and disposition of bavachin.

6.
Xenobiotica ; 50(8): 997-1008, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32116078

RESUMO

Corylifol A (CA), a phenolic compound from Psoralea corylifolia, possessed several biological properties but poor bioavailability. Here we aimed to investigate the roles of cytochromes P450s (CYPs), UDP-glucuronosyltransferases (UGTs) and efflux transporters in metabolism and disposition of CA.Metabolism of CA was evaluated in HLM, expressed CYPs and UGTs. Chemical inhibitors and shRNA-mediated gene silencing of multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP) were performed to assess the roles of transporters in CA disposition.Three oxidated metabolites (M1-M3) and two glucuronides (M4-M5) were detected. The intrinsic clearances (CLint) values of M1 and M4 in HLM were 48.10 and 184.03 µL/min/mg, respectively. Additionally, CYP1A1, 2C8 and 2C19 were identified as main contributors with CLint values of 13.01-49.36 µL/min/mg, while UGT1A1, 1A7, 1A8 and 1A9 were with CLint values ranging from 85.01 to 284.07 µL/min/mg. Furthermore, activity correlation analysis proved CYP2C8, UGT1A1 and 1A9 were the main active hepatic isozymes. Besides, rats and monkeys were appropriate model animals. Moreover, dipyridamole and MK571 both could significantly inhibit M4 efflux. Gene silencing results also indicated MRP4 and BCRP were major contributors in HeLa1A1 cells.Taken together, CYPs, UGTs, MRP4 and BCRP were important determinants of CA pharmacokinetics.


Assuntos
Flavonas/metabolismo , Animais , Transporte Biológico , Sistema Enzimático do Citocromo P-450/metabolismo , Glucuronosiltransferase/metabolismo , Células HeLa , Humanos , Psoralea , Ratos
7.
PLoS One ; 14(5): e0217695, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31150474

RESUMO

Demethoxycurcumin (DMC) is a safe and natural food-coloring additive, as well as an agent with several therapeutic properties. However, extensive glucuronidation in vivo has resulted in its poor bioavailability. In this study, we aimed to investigate the formation of DMC-O-glucuronides by uridine 5'-diphospho-glucuronosyltransferase 1A1 (UGT1A1) and its transport by breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs) in HeLa cells stably transfected with UGT1A1 (named HeLa1A1 cells). The chemical inhibitors Ko143 (a selective BCRP inhibitor) and MK571 (a pan-MRP inhibitor) both induced an obvious decrease in the excretion rate of DMC-O-glucuronides and a significant increase in intracellular DMC-O-glucuronide concentrations. Furthermore, BCRP knock-down resulted in a marked reduction in the level of excreted DMC-O-glucuronides (maximal 55.6%), whereas MRP1 and MRP4 silencing significantly decreased the levels of excreted DMC-O-glucuronides (a maximum of 42.9% for MRP1 and a maximum of 29.9% for MRP3), respectively. In contrast, neither the levels of excreted DMC-O-glucuronides nor the accumulation of DMC-O-glucuronides were significantly altered in the MRP4 knock-down HeLa cells. The BCRP, MRP1 and MRP3 transporters were identified as the most important contributors to the excretion of DMC-O-glucuronides. These results may significantly contribute to improving our understanding of mechanisms underlying the cellular disposition of DMC via UGT-mediated metabolism.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Diarileptanoides/farmacologia , Glucuronosiltransferase/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Neoplasias/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Disponibilidade Biológica , Diarileptanoides/química , Dicetopiperazinas/farmacologia , Corantes de Alimentos/química , Corantes de Alimentos/farmacologia , Inativação Gênica , Glucuronídeos/biossíntese , Glucuronídeos/genética , Glucuronosiltransferase/química , Células HeLa , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Propionatos/farmacologia , Transporte Proteico/genética , Quinolinas/farmacologia , Transfecção
8.
Front Pharmacol ; 10: 496, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31133859

RESUMO

Fraxetin, a natural compound present in many dietary supplements and herbs, is useful in the treatment of acute bacillary dysentery and type 2 diabetes. Previously, several metabolic studies have revealed extensive first-pass metabolism causing formation of fraxetin-O-glucuronides (G1 and G2), resulting in poor bioavailability of fraxetin. Active transport processes play an important role in the excretion of fraxetin-O-glucuronides. Nevertheless, the transporters involved are yet to be elucidated. In this study, we aimed to determine the active efflux transporters, including breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs), involved in the excretion of fraxetin-O-glucuronides. A chemical inhibitor, MK571 (5 and 20 µM), a pan-MRP inhibitor, led to a significant decrease in excreted G1 (maximal 59.1%) and G2 levels (maximal 42.4%), whereas Ko143 (5 and 20 µM), a selective BCRP inhibitor, caused moderate downregulation of excreted G1 (maximal 29.4%) and G2 (maximal 28.5%). Furthermore, MRP3 silencing resulted in a marked decrease of excretion rates (by 29.1% for G1 and by 21.1% for G2) and of fraction metabolized (f met; by 24.1% for G1 and by 18.6% for G2). Similar results, i.e., a significant reduction in excretion rates (by 34.8% for G1 and by 32.3% for G2) and in f met (by 22.7% for G1 and by 23.1% for G2) were obtained when MRP4 was partially silenced. No obvious modifications in the excretion rates, intracellular levels, and f met values of glucuronides were observed after short hairpin RNA (shRNA)-mediated silencing of transporters BCRP and MRP1. Taken together, our results indicate that MRP3 and MRP4 contribute more to the excretion of fraxetin-O-glucuronides than the other transporters do.

9.
Biofactors ; 44(6): 558-569, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30334318

RESUMO

Bisdemethoxycurcumin (BDMC) was a natural curcuminoid with many bioactivities present in turmeric (Curcuma longa L.). However, the disposition mechanisms of BDMC via uridine 5'-diphospho-glucuronosyltransferase (UGT) metabolism still remain unclear. Therefore, we aimed to determine the potential efflux transporters for the excretion of BDMC-O-glucuronide. Herein, chemical inhibition assays (Ko143, MK571, dipyridamole, and leukotriene C4) and biological inhibition experiments including stable knocked-down of breast cancer resistance protein (BCRP), multidrug resistance-associated proteins (MRPs) transporters were both performed in a HeLa cell line stably overexpressing UGT1A1 established previously. The results indicated that Ko143 (5 and 20 µM) caused a marked reduction in excretion rate (18.4-55.6%) and elevation of intracellular BDMC-O-glucuronide (28.8-48.1%), whereas MK-571 (5 and 20 µM) resulted in a significant decrease in excretion rate (6.2-61.6%) and increase of intracellular BDMC-O-glucuronide (maximal 27.1-32.6%). Furthermore, shRNA-mediated silencing of BCRP transporter led to a marked reduction in the excretion rate (21.1-36.9%) and an obvious elevation of intracellular glucuronide (24.9%). Similar results were observed when MRP1 was partially silenced. In addition, MRP3 and MRP4 silencing both displayed no obvious changes on the excretion rate and intracellular levels of glucuronide. In conclusion, chemical inhibition and gene silencing results both indicated that generated BDMC-O-glucoside were excreted primarily by the BCRP and MRP1 transporters. © 2018 BioFactors, 44(6):558-569, 2018.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Curcumina/metabolismo , Glucuronídeos/metabolismo , Glucuronosiltransferase/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Neoplasias/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transporte Biológico/efeitos dos fármacos , Curcumina/análogos & derivados , Estradiol/farmacologia , Regulação da Expressão Gênica , Glucuronosiltransferase/metabolismo , Ácido Glicirretínico/farmacologia , Células HeLa , Humanos , Cinética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Plasmídeos/química , Plasmídeos/metabolismo , Pirimidinas/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Sapogeninas/farmacologia , Transfecção
10.
Chem Biol Interact ; 296: 45-56, 2018 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-30237061

RESUMO

Cycloicaritin is a bioactive natural phenolic compound from Epimedium species. However, the glucuronidation and excretion which would influence oral bioavailability and pharmacokinetics of cycloicaritin still remain unknown. Here we aimed to establish UGT1A1 stably transfected HeLa cells, and to determine the contributions of BCRP and MRPs transporters to excretion of cycloicaritin-3-O-glucuronide. First, ß-estradiol was used to validate the expression of active UGT1A1 protein in engineered HeLa1A1 cells. Furthermore, Ko143 (5 and 20 µM) led to a significant decrease (42.4%-63.8%, p < 0.01) in CICT-3-G excretion and obvious accumulation (19.7%-54.2%, p < 0.05) of intracellular CICT-3-G, while MK571 (5 and 20 µM) caused a significant reduction (46.8%-64.8%, p < 0.05) in the excretion and obvious elevation (50.7%-85.2%, p < 0.01) of intracellular level of CICT-3-G. Furthermore, BCRP knocked-down brought marked reduction in excretion rates of CICT-3-G (26.0%-42.2%, p < 0.01), whereas MRP1 and MRP4-mediated silencing led to significant decrease in the excretion of CICT-3-G (23.8%-35.4%, p < 0.05 for MRP1 and 11.9%-16.0%, p < 0.05 for MRP4). By contrast, neither CICT-3-G excretion nor CICT-3-G accumulation altered in MRP3 knocked-down cells as compared to scramble cells. Taken together, BCRP, MRP1 and MRP4 were identified as the most important contributors for CICT-3-G excretion. Meanwhile, the UGT1A1 modified HeLa cells were a simple and practical tool to study UGT1A1-mediated glucuronidation and to characterize BCRP and MRPs-mediated glucuronide transport at a cellular level.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Glucuronídeos/metabolismo , Glucuronosiltransferase/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/química , Cromatografia Líquida de Alta Pressão , Glucuronídeos/química , Glucuronosiltransferase/biossíntese , Células HeLa , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/química , Proteínas de Neoplasias/química
11.
Arch Gynecol Obstet ; 298(5): 861-871, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30220024

RESUMO

OBJECTIVE: The aim of this meta-analysis is to explore the beneficial role of granulocyte colony-stimulating factor (G-CSF) on infertile women under artificial reproduction technology treatment. METHOD: Medline, Embase and ISI Web of Science databases were searched to identify relevant randomized control trials. Studies before July, 2017 were included for primary screening. Meta-analysis of the total and subgroup patients was conducted, and relative risks (RRs) and their 95% confidence intervals (95% CI) were calculated by a fixed-effect model if no heterogeneity (evaluated as I2 statistic) existed. Otherwise, a random-effects model was adopted. Subgroup analysis was performed by administrating route or clinical indication. Egger test and influence analysis were conducted to evaluate the publication bias and study power, respectively. RESULTS: The final selection enrolled 10 RCTs, involving 1016 IVF-ET cycles (521 distributed to the G-CSF group and 495 to the control). Compared with control group, G-CSF administration could significantly improve clinical pregnancy rate (CPR, RR 1.89, 95% CI 1.53-2.33), while it had no beneficial effect on embryo implantation rate (IR, RR 1.84, 95% CI 0.84-4.03). The subgroup analysis by administration route showed that both uterine infusion and subcutaneous injection can produce a substantial increase in CPR, with the pooled RRs (95% CI) 1.46 (1.04-2.05) and 2.23 (1.68-2.95), respectively. Nevertheless, most of included RCTs dealt with the RIF subjects, and the pooled analysis of this data showed a higher PR and IR in G-CSF group as compared to that in the control, with the RRs (95% CI) 2.07 (1.64-2.61) and 1.52 (1.08-2.14), respectively. Egger regression test did not demonstrate any significance for the publication bias. CONCLUSION: G-CSF administration has a beneficial role on the clinical outcome after embryo transfer by both routes of local infusion and systematic administration, especially for the cases with RIF. Further RCTs are needed to investigate the role of G-CSF in thin endometrium patients.


Assuntos
Transferência Embrionária/métodos , Fertilização In Vitro/métodos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Infertilidade Feminina/tratamento farmacológico , Adulto , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Humanos , Infertilidade Feminina/patologia , Gravidez
12.
J Pharm Biomed Anal ; 158: 351-360, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-29933228

RESUMO

Neobavaisoflavone (NBIF), a phenolic compound isolated from Psoralea corylifolia L., possesses several significant biological properties. However, the pharmacokinetic behaviors of NBIF have been characterized as rapid oral absorption, high clearance, and poor oral bioavailability. We found that NBIF underwent massive glucuronidation and oxidation by human liver microsomes (HLM) in this study with the intrinsic clearance (CLint) values of 12.43, 10.04, 2.01, and 6.99 µL/min/mg for M2, M3, M4, and M5, respectively. Additionally, the CLint values of G1 and G2 by HLM were 271.90 and 651.38 µL/min/mg, respectively, whereas their respective parameters were 59.96 and 949.01 µL/min/mg by human intestine microsomes (HIM). Reaction phenotyping results indicated that CYP1A1, 1A2, 2C8, and 2C19 were the main contributors to M4 (34.96 µL/min/mg), M3 (29.45 µL/min/mg), M3 (13.16 µL/min/mg), and M2 (63.42 µL/min/mg), respectively. UGT1A1, 1A7, 1A8, and 1A9 mainly catalyzed the formation of G1 (250.87 µL/min/mg), G2 (438.15 µL/min/mg), G1 (92.68 µL/min/mg), and G2 (1073.25 µL/min/mg), respectively. Activity correlation analysis assays showed that phenacetin-N-deacetylation was strongly correlated to M3 (r = 0.860, p = 0.003) and M4 (r = 0.775, p = 0.014) in nine individual HLMs, while significant activity correlations were detected between paclitaxel-6-hydroxylation and M2 (r = 0.675, p = 0.046) and M3 (r = 0.829, p = 0.006). There was a strong correlation between ß-estradiol-3-O-glucuronide and G1 (r = 0.822, p = 0.007) and G2 (r = 0.689, p = 0.040), as well as between propofol-O-glucuronidation and G1 (r = 0.768, p = 0.016) and G2 (r = 0.860, p = 0.003). Moreover, the phase I metabolism and glucuronidation of NBIF revealed marked species differences, and mice are the best animal model for investigating the metabolism of NBIF in humans. Taken together, characterization of NBIF-related metabolic pathways involving in CYP1A1, 1A2, 2C8, 2C19, and UGT1A1, 1A7, 1A8, 1A9 are helpful for understanding the pharmacokinetic behaviors and conducting in-depth pharmacological studies.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Glucuronosiltransferase/metabolismo , Isoflavonas/farmacocinética , Microssomos Hepáticos/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Ensaios Enzimáticos , Glucuronídeos/metabolismo , Haplorrinos , Humanos , Hidroxilação , Mucosa Intestinal/metabolismo , Intestinos/citologia , Fígado/citologia , Fígado/metabolismo , Camundongos , Oxirredução , Coelhos , Ratos , Especificidade da Espécie , Espectrometria de Massas em Tandem
13.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 36(2): 162-166, 2018 Apr 01.
Artigo em Chinês | MEDLINE | ID: mdl-29779277

RESUMO

OBJECTIVE: This study aims to study the effect of the improved partial denture treatment in the rehabilitation of patients with temporomandibular joint disorders (TMD). METHODS: Twenty middle-aged and old patients suffering from osteoarthrosis were treated with the improved partial denture treatment. These patients were followed up during the partial denture treatment and after the rehabilitation. Both the clinical symptoms and Fricton's craniomandibular index were used to evaluate the clinical effects. Data were analyzed using SPSS17.0. RESULTS: The effective rate reached 100% when the patients wore partial dentures for 1 month. All of the 20 patients were comfortable with temporomandibular joint, and they expressed ultimate satisfaction with the denture. The Fricton indexes of 20 patients decreased significantly after the treatment (P<0.05). CONCLUSIONS: Partial denture treatment is an ideal method in rehabilitation for patients with TMD (osteoarthrosis) and dentition defect.


Assuntos
Prótese Parcial , Transtornos da Articulação Temporomandibular , Dentição , Dentaduras , Humanos , Pessoa de Meia-Idade , Articulação Temporomandibular , Transtornos da Articulação Temporomandibular/reabilitação
14.
J Pharm Biomed Anal ; 155: 157-168, 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29631076

RESUMO

Corylin, an phenolic compound from Psoralea corylifolia, has been reported with various pharmacological properties but has poor bioavailability due to massive metabolism. In this study, twelve metabolites of corylin mainly involving in oxidation, hydration, glucuronidation and sulfation were detected in mice. Furthermore, the oxidation and hydration of corylin (M4) in human liver microsomes (HLM) and human intestine microsomes (HIM) were both efficient with high CLint (intrinsic clearance) values of 24.29 and 42.85 µL/min/mg, respectively. CYP1A1, 1B1 and 2C19 contributed most for M4 with the CLint values of 26.63, 33.09 and 132.41 µL/min/mg, respectively. Besides, M4 was strongly correlated with phenacetin-N-deacetylation (r = 0.885, p = 0.0001) and tolbutamide-4-oxidation (r = 0.727, p = 0.001) in twelve individual HLMs, respectively. In addition, corylin was efficiently glucuronidated (M7) in HLM (125.33 µL/min/mg) and in HIM (108.74 µL/min/mg). UGT1A1 contributed the most for M7 with the CLint value of 122.32 µL/min/mg. Meanwhile, M7 was significantly correlated with ß-estradiol-3-O-glucuronidation (r = 0.742, p = 0.006) in twelve individual HLMs. Moreover, the metabolism of corylin showed marked species differences. Taken together, corylin was subjected to massive first-pass metabolism in liver and intestine, while CYP1A1, 1B1, 2C19 and UGT1A1 were the main contributors. Finally, the proposed metabolic pathway of corylin involed CYP and UGT isoforms were summarized, which could help to understand the metabolic fate of corylin in vivo.


Assuntos
Flavonoides/metabolismo , Animais , Citocromo P-450 CYP1A1/metabolismo , Glucuronídeos/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Cinética , Fígado/metabolismo , Masculino , Metabolômica/métodos , Camundongos , Microssomos Hepáticos/metabolismo , Fenóis/metabolismo , Especificidade da Espécie
15.
Stem Cell Reports ; 10(3): 808-821, 2018 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-29456182

RESUMO

Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death in young individuals. A potential role of mtDNA mutations in HCM is known. However, the underlying molecular mechanisms linking mtDNA mutations to HCM remain poorly understood due to lack of cell and animal models. Here, we generated induced pluripotent stem cell-derived cardiomyocytes (HCM-iPSC-CMs) from human patients in a maternally inherited HCM family who carry the m.2336T>C mutation in the mitochondrial 16S rRNA gene (MT-RNR2). The results showed that the m.2336T>C mutation resulted in mitochondrial dysfunctions and ultrastructure defects by decreasing the stability of 16S rRNA, which led to reduced levels of mitochondrial proteins. The ATP/ADP ratio and mitochondrial membrane potential were also reduced, thereby elevating the intracellular Ca2+ concentration, which was associated with numerous HCM-specific electrophysiological abnormalities. Our findings therefore provide an innovative insight into the pathogenesis of maternally inherited HCM.


Assuntos
Cardiomiopatia Hipertrófica/patologia , Células-Tronco Pluripotentes Induzidas/patologia , Mitocôndrias/patologia , Proteínas Mitocondriais/genética , Miócitos Cardíacos/patologia , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Cálcio/metabolismo , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Fenômenos Eletrofisiológicos/fisiologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Potencial da Membrana Mitocondrial/genética , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mutação/genética , Miócitos Cardíacos/metabolismo , RNA Ribossômico 16S/genética
16.
Food Funct ; 9(3): 1410-1423, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29318243

RESUMO

Active efflux transport of glucuronides out of cells is a critical process in elimination of drugs and food-derived compounds. Wushanicaritin, a natural polyphenol from Epimedium species, has shown many biological activities. However, the transporters responsible for excretion of wushanicaritin glucuronides still remain undefined. Herein, chemical inhibitors (Ko143, MK571, dipyridamole and leukotriene C4) and single stable knocked-down efflux transporters (BCRP, MRP1, MRP3 and MRP4) were used to determine the contributions of efflux transporters to glucuronide efflux and cellular glucuronidation in UGT1A1-overexpressing HeLa cells (HeLa1A1). Knock-down of transporters was performed by stable transfection of short hairpin RNA (shRNA) using lentiviral vectors. The HeLa1A1 cell lysate catalyzed wushanicaritin glucuronidation, generating wushanicaritin-3-O-glucuronide and wushanicaritin-7-O-glucuronide. Ko143 (a dual inhibitor of BCRP, 5-20 µM) caused a marked decrease in excretion rate (maximal 53.4%) and increase of intracellular glucuronides (maximal 86.0%), while MK-571 (an inhibitor of MRPs, 5-20 µM) resulted in a significant reduction in excretion rate (maximal 64.6%) and rise of intracellular glucuronides (maximal 98.0%). By contrast, dipyridamole and leukotriene C4 showed no inhibitory effects on glucuronide excretion. Furthermore, shRNA-mediated silencing of a target transporter led to a marked reduction in the excretion rate of wushanicaritin glucuronides (maximal 33.8% for BCRP; 25.9% for MRP1; 26.7% for MRP3; 39.3% for MRP4). Transporter silencing also led to substantial decreases in efflux clearance (maximal 61.5% for BCRP; 48.7% for MRP1; 35.1% for MRP3; 63.1% for MRP4). In conclusion, chemical inhibition and gene silencing results suggested that BCRP, MRP1, MRP3 and MRP4 were significant contributors to excretion of wushanicaritin glucuronides.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Medicamentos de Ervas Chinesas/metabolismo , Flavonoides/metabolismo , Glucuronídeos/metabolismo , Glucuronosiltransferase/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Transporte Biológico/efeitos dos fármacos , Dicetopiperazinas/farmacologia , Dipiridamol/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Epimedium/química , Flavonoides/farmacologia , Técnicas de Silenciamento de Genes , Inativação Gênica , Glucuronosiltransferase/genética , Células HeLa , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Neoplasias/genética , Propionatos/farmacologia , Quinolinas/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo
17.
Guang Pu Xue Yu Guang Pu Fen Xi ; 36(8): 2607-12, 2016 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-30074373

RESUMO

A set of coal samples were used for laser-induced breakdown spectroscopy (LIBS) experiment to measure the coal calorific value. Traditional channel normalization method didn't consider the physical / chemical mechanism of coal, which would limit the model in precision, accuracy and repeatability. Thus a new calibrated model based on the kinds of the effects of spectral deviation was proposed in this paper. The model selected 19 groups of coal samples, where the random 15 groups were used to establish quantitative analysis model of calorific value while the remaining four for inspection and evaluation. The model based on spectral deviation factors, and the transmission theory combined with the stark broadening formula was used to deduce the absorption effect mechanism and the deviation correction method under the condition of LIBS. The mutual interference between elements and the mechanism of matrix effect were being analyzed while K coefficient method was used to correct mutual interference between the elements in the LIBS. The establishment of numerical model with the electron density, the plasma temperature and the element concentration was used to deeply corrected spectrum deviation caused by matrix effect. Thus taking into consideration of the effect of self-absorption, interfere of inter-elements and matrix effect, the calibration model was established, while R2=0.967, RMSEP=0.49 MJ·kg-1, RMSE=0.45 MJ·kg-1, MRE=2.42%, ARE=1.64%, RSD=5.79% and RSDP=8.10%. Compared with the 0.405, 8.28 MJ·kg-1, 4.14 MJ·kg-1, 22.85%, 52.48%, 18.28% and 32.85% of traditional channel normalized-multiple linear regression method, it demonstrated that the precision and accuracy have been improved significantly and model has good application value.

18.
Methods Mol Biol ; 1353: 323-42, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25646615

RESUMO

Mitochondrial disease is a group of disorders caused by dysfunctional mitochondria, of which the mutation in the mitochondrial DNA is one of the primary factors. However, the molecular pathogenesis of mitochondrial diseases remains poorly understood due to lack of cell models. Patient-specific induced pluripotent stem cells (iPS cells or iPSCs) are originated from individuals suffering different diseases but carrying unchanged disease causing gene. Therefore, patient-specific iPS cells can be used as excellent cell models to elucidate the mechanisms underlying mitochondrial diseases. Here we present a detailed protocol for generating iPS cells from urine cells and fibroblasts for instance, as well as a series of characterizations.


Assuntos
Reprogramação Celular , DNA Mitocondrial/genética , Fibroblastos/citologia , Células-Tronco Pluripotentes Induzidas/citologia , Doenças Mitocondriais/patologia , Neurônios/citologia , Animais , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Derme/citologia , Derme/metabolismo , Corpos Embrioides/citologia , Corpos Embrioides/efeitos dos fármacos , Corpos Embrioides/metabolismo , Células Alimentadoras/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Cultura Primária de Células , Retroviridae/genética , Teratoma/genética , Teratoma/metabolismo , Teratoma/patologia , Urina/citologia
19.
J Med Genet ; 51(3): 176-84, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24367055

RESUMO

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a primary disorder characterised by asymmetric thickening of septum and left ventricular wall, with a prevalence of 0.2% in the general population. OBJECTIVE: To describe a novel mitochondrial DNA mutation and its association with the pathogenesis of HCM. METHODS AND RESULTS: All maternal members of a Chinese family with maternally transmitted HCM exhibited variable severity and age at onset, and were implanted permanent pacemakers due to complete atrioventricular block (AVB). Nuclear gene screening (MYH7, MYBPC3, TNNT2 and TNNI3) was performed, and no potential pathogenic mutation was identified. Mitochondrial DNA sequencing analysis identified a novel homoplasmic 16S rRNA 2336T>C mutation. This mutation was exclusively present in maternal members and absent in non-maternal members. Conservation index by comparison to 16 other vertebrates was 94.1%. This mutation disturbs the 2336U-A2438 base pair in the stem-loop structure of 16S rRNA domain III, which is involved in the assembly of mitochondrial ribosome. Oxygen consumption rate of the lymphoblastoid cells carrying 2336T>C mutation had decreased by 37% compared with controls. A reduction in mitochondrial ATP synthesis and an increase in reactive oxidative species production were also observed. Electron microscopic analysis indicated elongated mitochondria and abnormal mitochondrial cristae shape in mutant cells. CONCLUSIONS: It is suggested that the 2336T>C mutation is one of pathogenic mutations of HCM. This is the first report of mitochondrial 16S rRNA 2336T>C mutation and an association with maternally inherited HCM combined with AVB. Our findings provide a new insight into the pathogenesis of HCM.


Assuntos
Cardiomiopatia Hipertrófica/genética , Proteínas Mitocondriais/genética , Mutação/genética , RNA Ribossômico 16S/genética , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo
20.
Curr Stem Cell Res Ther ; 9(2): 134-40, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24372327

RESUMO

Mitochondrial diseases are clinical phenotypes associated with mitochondrial dysfunction, which can be caused by mutations of mitochondrial DNA (mtDNA) or of nuclear genes. Since there are no high-performance transfect systems yet to make particular mtDNA mutation, and tissue sources are limited by ethical issue and injury, the molecular pathogenesis of mitochondrial diseases remains poorly understood. The generation of induced pluripotent stem (iPS) cells from adult somatic cells has opened a remarkable avenue for theoretic study and therapeutic application. Patient-specific induced pluripotent stem cells and differentiated cells derived from them are attracting increasing attention to elucidate the mechanisms underlying mitochondrial diseases. In this review, we summarize the advances of iPS cells, advantages of patient- specific iPS cells as a novel disease model, especially in mitochondrial disease. Occurring challenges and perspectives of patient-specific iPS cells research are also discussed.


Assuntos
Células-Tronco Pluripotentes Induzidas/fisiologia , Doenças Mitocondriais/patologia , Animais , Células Cultivadas , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Modelos Biológicos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...