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1.
Fitoterapia ; 137: 104199, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31175950

RESUMO

Human carboxylesterase 1 (CES1), primarily expressed in the liver and adipocytes, is responsible for the hydrolysis of endogenous esters (such as cholesteryl esters and triacylglycerols) and the metabolism of xenobiotic esters (such as clopidogrel and oseltamivir), thus participates in physiological and pathological processes. In this study, a series of natural pentacyclic triterpenoids were collected and their inhibitory effects against CES1 and CES2 were assayed using D-luciferin methyl ester (DME) and N-(2-butyl-1,3-dioxo-2,3-dihydro-1H-benzo[de] isoquinolin- 6-yl)- 2-chloroacetamide (NCEN) as specific optical substrate for CES1, and CES2, respectively. To this end, betulinic acid (BA) was found with strong inhibitory effect on CES1 (IC50, 15 nM) and relative high selectivity over CES2 (>2400-fold). Primary structure-activity relationships (SAR) analysis and docking simulations revealed that the carboxyl group at the C-28 site of BA is very essential for CES1 inhibition. The inhibition kinetic analyses demonstrated that BA was a potent competitive inhibitor against CES1-mediated DME hydrolysis. Further investigation on the inhibitory effect of BA in living cells (HepG2) based assays demonstrated that BA displayed potent inhibitory effects on intracellular CES1 activities, with the low IC50 value of 1.30 µM. These results demonstrated that BA is potent and highly selective CES1 inhibitor, which might be used as the promising tool for exploring the biological functions of CES1 in complex biological systems.


Assuntos
Hidrolases de Éster Carboxílico/antagonistas & inibidores , Triterpenos/farmacologia , Células Hep G2 , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
2.
World J Gastroenterol ; 25(17): 2099-2109, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31114136

RESUMO

BACKGROUND: The methylated septin 9 (mSEPT9) assay was the first blood-based test approved by the United States Food and Drug Administration as a colorectal screening test. However, the diagnostic and prognostic role of preoperative mSEPT9 for colorectal cancer (CRC) in Chinese patients is still unknown. AIM: To improve the understanding of diagnostic and prognostic factors, serum mSEPT9 was detected in Chinese CRC patients. METHODS: A retrospective analysis of 354 cases, of which 300 had CRC and 54 were normal, was performed in China. Patients' characteristics, treatments, and laboratory data, including age, the date of surgery, Union for International Cancer Control (UICC) stages, distant metastasis (M), and so on, were collected. Methylation levels of SEPT9 were quantified by quantitative, methylation-specific polymerase chain reaction before surgery. In addition, the effects of mSEPT9 on the occurrence and prognosis of 330 CRC cases from The Cancer Genome Atlas (TCGA) database were evaluated using bioinformatics analyses. Potential prognostic factors for overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier univariate analysis. RESULTS: In Chinese CRC patients, positive mSEPT9 was strongly associated with advanced UICC stages, deeper invasion by the primary tumor, and more distant metastasis. Methylation levels of SEPT9 were stage-dependent and showed a stepwise increase in UICC stages (I-IV), primary tumor categories (T1-T4), regional node categories (N0-N2), and distant metastasis categories (M0-M1). The patients with positive mSEPT9 showed a tendency toward lower PFS. After analyzing TCGA clinical data, the high mSEPT9 group was found to be obviously correlated only with more distant metastasis. The patients with high mSEPT9 levels showed a tendency toward lower OS. Besides, nine meaningful mSEPT9 sites were found to provide guidance for the follow-up studies. CONCLUSION: MSEPT9 analysis may add valuable information to current tumor staging. Serum mSEPT9 in Chinese CRC patients appears to offer promising novel prognostic markers and might be considered for monitoring CRC recurrence.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/diagnóstico , Septinas/metabolismo , Adenoma/sangue , Adenoma/diagnóstico , Adenoma/cirurgia , Idoso , China , Neoplasias Colorretais/sangue , Neoplasias Colorretais/cirurgia , Biologia Computacional , Metilação de DNA , Detecção Precoce de Câncer , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Período Pré-Operatório , Prognóstico , Estudos Retrospectivos
3.
Zhongguo Zhong Yao Za Zhi ; 44(3): 566-573, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-30989924

RESUMO

This study investigated the inhibitory effect of eight natural flavonoids in Chinese herb Scutellariae Radix on huamn cytochrome P450 1 A(CYP1 A), a key cancer chemo-preventive target. In this study, phenacetin was used as a probe substrate for CYP1 A, while human liver microsomes and recombinant human CYP1 A enzymes were used as enzyme sources. Liquid chromatography-tandem mass spectrometry was used to monitor the formation rates of acetaminophen, the O-deethylated metabolite of phenacetin. The dose-dependent inhibition curves were depicted based on the changes of the formation rates of acetaminophen, while the IC_(50) were determined. Inhibition kinetic analyses and docking simulations were used to investigate the inhibition modes and mechanism of wogonin(the most potent CYP1 A inhibitor in this herb), while the inhibition constants(K_i) of wogonin against both CYP1 A1 and CYP1 A2 were determined. Among all tested flavonoids, wogonin, 7-methoxyflavanone and oroxylin A displayed a strong inhibitory effect on CYP1 A(IC_(50)<1 µmol·L~(-1)), baicalein exhibited a moderate inhibitory effect on CYP1 A(IC_(50) between 1-10 µmol·L~(-1)), and baicalin, scutellarein and wogonoside displayed a very weak inhibitory effect on CYP1 A(IC_(50) between 10-25 µmol·L~(-1)), but scutellarin displayed a negligible inhibitory effect on CYP1 A(IC_(50)>100 µmol·L~(-1)). Further investigations demonstrated that wogonin had a weak inhibitory effect on other human CYP enzymes, suggesting that it could be used as a lead compound for the development of specific inhibitors of CYP1 A. Furthermore, the inhibition kinetic analyses clearly demonstrated that wogonin could strongly inhibit phenacetin O-deethylation in both CYP1 A1 and CYP1 A2 in a competitive manner, with K_i values at 0.118 and 0.262 µmol·L~(-1), respectively. Molecular docking demonstrated that wogonin could strongly interact with CYP1 A1 and CYP1 A2 via hydrophobic and π-π interactions, as well as Ser120 and Ser116 in CYP1 A1 via hydrogen-bonding. In conclusion, this study found that some flavonoids in Scutellariae Radix displayed a strong inhibitory effect on CYP1 A, while wogonin is the most potent CYP1 A inhibitor with a relatively high selectivity towards CYP1 A over other human CYPs.


Assuntos
Citocromo P-450 CYP1A1/antagonistas & inibidores , Flavanonas/farmacologia , Flavonoides/farmacologia , Scutellaria baicalensis/química , Cromatografia Líquida , Inibidores das Enzimas do Citocromo P-450/farmacologia , Humanos , Simulação de Acoplamento Molecular
4.
Front Pharmacol ; 10: 52, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30778299

RESUMO

Bufotalin (BFT), one of the naturally occurring bufodienolides, has multiple pharmacological and toxicological effects including antitumor activity and cardiotoxicity. This study aimed to character the metabolic pathway(s) of BFT and to identify the key drug metabolizing enzyme(s) responsible for hepatic metabolism of BFT in human, as well as to explore the related molecular mechanism of enzymatic selectivity. The major metabolite of BFT in human liver microsomes (HLMs) was fully identified as 5ß-hydroxylbufotalin by LC-MS/MS and NMR techniques. Reaction phenotyping and chemical inhibition assays showed that CYP3A4 and CYP3A5 were key enzymes responsible for BFT 5ß-hydroxylation. Kinetic analyses demonstrated that BFT 5ß-hydroxylation in both HLMs and human CYP3A4 followed the biphasic kinetics, while BFT 5ß-hydroxylation in CYP3A5 followed substrate inhibition kinetics. Furthermore, molecular docking simulations showed that BFT could bind on two different ligand-binding sites on both CYP3A4 and CYP3A5, which partially explained the different kinetic behaviors of BFT in CYP3A4 and CYP3A5. These findings are very helpful for elucidating the phase I metabolism of BFT in human and for deeper understanding the key interactions between CYP3A enzymes and bufadienolides, as well as for the development of bufadienolide-type drugs with improved pharmacokinetic and safety profiles.

5.
Toxicol In Vitro ; 44: 280-286, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28647665

RESUMO

DDAB (6,8-dichloro-9,9-dimethyl-7-oxo-7,9-dihydroacridin-2-yl benzoate) is a newly developed near-infrared fluorescent probe for human carboxylesterase 2 (hCE2), exhibiting high specificity and good reactivity for real-time monitoring the enzymatic activities of hCE2 in complex biological systems. In order to explore the applicability of DDAB in commonly used animal species, the interspecies difference in DDAB hydrolysis was carefully investigated by using liver microsomes from human and five experimental animals including mouse, rat, dog, minipig and monkey. Metabolite profiling demonstrated that DDAB hydrolysis could be catalyzed by all tested liver microsomes from different animals but displayed significant difference in the reaction rate. Chemical inhibition assays demonstrated that carboxylesterases (CEs) were the major enzymes involved in DDAB hydrolysis in all tested liver microsomes, indicating that DDAB was a selective substrate of CEs in a variety of mammals. However, the differential effects of loperamide (LPA, a specific inhibitor against hCE2) on DDAB hydrolysis among various species were observed. The apparent kinetic parameters and the maximum intrinsic clearances (CLmax) for DDAB hydrolysis in liver microsomes from different animals were determined, and the order of CLmax values for the formation of DDAO was CyLM>MLM≈PLM>RLM>HLM≈DLM. These findings were helpful for the rational use of DDAB as an imaging tool for CE2 in different mammals, as well as for translational researches on the function of mammalian CEs and CE2-associated drug-drug interactions.


Assuntos
Acridinas/metabolismo , Acridinas/farmacologia , Benzoatos/metabolismo , Benzoatos/farmacologia , Corantes Fluorescentes/farmacologia , Microssomos Hepáticos/metabolismo , Animais , Cães , Humanos , Hidrólise , Masculino , Camundongos Endogâmicos ICR , Ratos Sprague-Dawley , Especificidade da Espécie , Suínos , Porco Miniatura
6.
Asian-Australas J Anim Sci ; 30(12): 1679-1683, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28423874

RESUMO

OBJECTIVE: An experiment was conducted to study the association between the single nucleotide polymorphisms (SNPs) in 5'-untranslated regions (5'-UTR) of equine chorionic gonadotropin (eCG) genes and the serum eCG levels. METHODS: SNPs in 5'-UTR of eCG genes were screened across 10 horse breeds, including 7 Chinese indigenous breeds and 3 imported breeds using iPLEX chemistry, and the association between the serum eCG levels of 174 pregnant Da'an mares and their serum eCG levels (determined with ELISA) was analyzed. RESULTS: Four SNPs were identified in the 5'-UTR of the eCGα gene, and one of them was unique in the indigenous breeds. There were 2 SNPs detected at the 5' end of the eCGß subunit gene, and one of them was only found in the Chinese breeds. The SNP g.39948246T>C at the 5'-UTR of eCGα was associated significantly with eCG levels of 75-day pregnant mare serum (p<0.05) in Da'an mares. Prediction analysis on binding sites of transcription factors showed that the g.39948246T>C mutation causes appearance of the specific binding site of hepatocyte nuclear factor 3 forkhead homolog 2 (HFH-2), which is a transcriptional repressor belonging to the forkhead protein family of transcription factors. CONCLUSION: The SNP g.39948246T>C at the 5'-UTR of eCGα is associated with eCG levels of 75-day pregnant mare serum (p<0.05).

7.
Epilepsy Res ; 132: 64-69, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28315807

RESUMO

OBJECTIVE: To explore the influence of CYP2C9, CYP2A6, ACSM2A, CPT1A gene polymorphisms on valproic acid (VPA) and its role in metabolism-related liver dysfunction in order to guide the clinical safety and rational use of VPA. METHODS: One hundred two patients taking sodium valproate oral solution were genotyped. To assess the genotypes of relevant genes, the CYP2C9 gene was directly sequenced; for polymorphism classification, multiple Long-PCR electrophoresis was conducted for CYP2A6; and imLDR method was used for ACSM2A and CPT1A. GC-MS-SIM was used to determine the levels of VPA and 2-propyl-4-pentenoic acid (4-ene-VPA) in human plasma simultaneously. RESULTS: CYP2C9 mutations had a significant impact on 4-ene-VPA concentration, in patients with wild-type CYP2C9 (CYP2C9*1), which has a greater capacity for VPA metabolism than the mutant type (CYP2C9*3), liver dysfunction was substantially higher. Patients with an ACSM2A polymorphism had higher levels of ALT and AST compared with wild-type (p<0.05), but the mutations had no effect on the VPA-related liver dysfunction (p>0.05). Among different CYP2A6 and CPT1A genotype groups, there was no significant correlation in the levels of VPA, 4-ene-VPA, ALT, AST or TB (p>0.05). The content of 4-ene-VPA had no direct correlation with the incidence of liver dysfunction. CONCLUSIONS: Early detection of CYP2C9 gene polymorphisms may help to predict or prevent liver dysfunction caused by VPA. While the concentration of 4-ene-VPA was not suitable as an early warning index, the results provide clear theoretical guidance for the rational and safe clinical use of VPA.


Assuntos
Anticonvulsivantes/efeitos adversos , Citocromo P-450 CYP2C9/genética , Epilepsia/genética , Mutação/genética , Polimorfismo Genético/genética , Ácido Valproico/efeitos adversos , Anticonvulsivantes/uso terapêutico , Grupo com Ancestrais do Continente Asiático , Carnitina O-Palmitoiltransferase/genética , Coenzima A Ligases/genética , Citocromo P-450 CYP2A6/genética , Epilepsia/tratamento farmacológico , Feminino , Genótipo , Humanos , Masculino , Ácido Valproico/uso terapêutico
8.
Yao Xue Xue Bao ; 52(1): 26-33, 2017 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-29911373

RESUMO

Cytochrome P4502J2 (CYP2J2) is widely distributed in various human tissues and takes a part in the metabolism of endogenous compounds and drugs. CYP2J2 can convert arachidonic acid (AA) to expoxyeicosatrienoic acids (EETs), which have various biological effects, implying the important role of CYP2J2 in the regulation of cardiovascular system and promotion of tumor progression and metastasis. Additionally, CYP2J2 plays an indispensable role in the intestinal metabolism of various drugs, such as astemizole, terfenadine and ebastine. In this review, the metabolic function, characteristic of catalysis and tissue distribution of CYP2J2 are discussed with the latest literatures both in China and abroad. The state-of-the-art methods for characterization of CYP2J2 and current trend of substrate discovery as well as its relationship with disease are highlighted. This review gives in-depth understanding of the function of CYP2J2 and its role in disease advance. The information of ligand (substrate and inhibitor) will provide the theoretical guidance and reference to the development of novel drugs for CYP2J2.


Assuntos
Sistema Enzimático do Citocromo P-450/fisiologia , Ácido Araquidônico , Inibidores das Enzimas do Citocromo P-450 , Humanos , Ligantes
9.
J Pharm Pharm Sci ; 18(3): 256-65, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26517132

RESUMO

PURPOSE: Oxcarbazepine (OXC) is widely used in anti-epileptic treatment. Cytochrome P450 3A4 (CYP3A4), cytochrome P450 3A5(CYP3A5), and ATP-binding cassette sub-family B member 1 (ABCB1) are potential genes involved in OXC metabolisms and transport in vivo. This study aims to examine the genetic effects of CYP3A4, CYP3A5, and ABCB1 on OXC metabolism and transport in Chinese epileptic patients using OXC as monotherapy and bitherapy with lamotrigine (LTG), levetiracetam (LEV), or valproic acid (VPA). METHODS: Sixty-six Chinese epileptic patients were recruited from Xiangya Hospital Central South University, of whom 40 patients were receiving OXC monotherapy, 11 patients were placed in the OXC bitherapy group combined with one enzyme-inducing anti-epileptic drugs (LTG or LEV), and 15 patients were placed in the OXC bitherapy group combined with VPA. Oxcarbazepine and its main metabolite 10-hydrocarbazepine (MHD) plasma concentrations were measured using high performance liquid chromatography (HPLC)-UV method. In addition, eight single nucleotide polymorphisms (SNPs) in CYP3A4, CYP3A5, ABCB1 gene were genotyped by polymerase chain reaction-improved multiple ligase detection reaction (PCR-iMLDR). RESULTS: In the OXC+VPA group, ABCB1 rs2032582 and rs2032582-rs10234411-rs1045642 TAG haplotype were associated with MHD and MHD+OXC plasma concentration before permutation test. In OXC monotherapy and OXC+ LTG/LEV groups, no significant association between genetic polymorphisms in CYP3A4/5, ABCB1 gene and OXC plasma concentration parameters were observed. CONCLUSION: CYP3A4/5 and ABCB1 genetic variants might not take part in the metabolism and transport of MHD and OXC among epileptic patients using OXC monotherapy and bitherapy in combination with LEV, LTG or VPA.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Carbamazepina/análogos & derivados , Citocromo P-450 CYP3A/genética , Epilepsia/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adolescente , Adulto , Anticonvulsivantes/administração & dosagem , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/fisiologia , Carbamazepina/administração & dosagem , Carbamazepina/sangue , Criança , Quimioterapia Combinada , Epilepsia/sangue , Epilepsia/tratamento farmacológico , Feminino , Humanos , Masculino , Oxcarbazepina , Polimorfismo de Nucleotídeo Único , Adulto Jovem
10.
Epilepsy Res ; 117: 52-7, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26421491

RESUMO

OBJECTIVE: To examine the effects of cytochrome P450 3A4 (CYP3A4), cytochrome P450 3A5 (CYP3A5) and ATP-binding cassette sub-family B member 1 (ABCB1) genetic polymorphisms on carbamazepine (CBZ) plasma concentrations in Chinese patients with epilepsy using CBZ as monotherapy and bitherapy with phenytoin (PHT), phenobarbital (PB), or valproic acid (VPA). METHODS: Eighty-eight Chinese patients with epilepsy were recruited from Xiangya Hospital Central South University, of whom 66 patients were placed in the CBZ monotherapy group, 10 patients were placed in the CBZ bitherapy group combined with one enzyme-inducing anti-seizure medications (PHT or PB), and 12 patients were placed in the CBZ bitherapy group combined with VPA. Carbamazepine and carbamazepine-10,11-epoxide (CBZ-E) plasma concentration of these patients were measured. In addition, the genetic polymorphisms of rs4646440 and rs2242480 in the CYP3A4 gene, rs15524 and rs776746 in the CYP3A5 gene, and rs1045642, rs2032582, rs10234411 and rs1128503 in the ABCB1 gene of the cohort were genotyped. Subsequently, the associations between CBZ plasma concentrations and target single-nucleotide polymorphisms (SNPs), as well as haplotypes, were analysed. RESULTS: In the CBZ monotherapy group, dose-adjusted CBZ concentrations were not associated with the eight SNPs and haplotypes. In the CBZ+PHT/PB group, rs776746, rs15524 and rs15524-rs776746 GT, AC haplotype were significantly associated with dose-adjusted CBZ plasma concentration (P=0.006, 0.006, 0.003, 0.003, respectively) and CBZ plus CBZ-E concentrations (P=0.006, 0.006, 0.006, 0.006, respectively); rs2032582, rs10234411 and rs2032582-rs10234411 AT, and CA haplotype were associated with the CBZ-E/CBZ ratio (P=0.007, 0.004, 0.004, 0.007, respectively). CONCLUSIONS: rs776746 and rs15524 in the CYP3A5 gene tend to affect CBZ metabolism, and rs2032582, rs10234411 in the ABCB1 gene may contribute to inter-individual variation in CBZ and in CBZ-E transport among patients with epilepsy using CBZ in combination with PHT or PB.


Assuntos
Anticonvulsivantes/uso terapêutico , Carbamazepina/uso terapêutico , Sistema Enzimático do Citocromo P-450/genética , Epilepsia/tratamento farmacológico , Epilepsia/genética , Polimorfismo de Nucleotídeo Único , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adolescente , Adulto , Anticonvulsivantes/farmacocinética , Carbamazepina/farmacocinética , Criança , China , Quimioterapia Combinada , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Fenobarbital/uso terapêutico , Fenitoína/uso terapêutico , Ácido Valproico/uso terapêutico , Adulto Jovem
11.
Chin J Nat Med ; 13(7): 507-20, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26233841

RESUMO

This paper reports a pharmacophylogenetic study of a medicinal plant family, Ranunculaceae, investigating the correlations between their phylogeny, chemical constituents, and pharmaceutical properties. Phytochemical, ethnopharmacological, and pharmacological data were integrated in the context of the systematics and molecular phylogeny of the Ranunculaceae. The chemical components of this family included several representative metabolic groups: benzylisoquinoline alkaloids, ranunculin, triterpenoid saponin, and diterpene alkaloids, among others. Ranunculin and magnoflorine were found to coexist in some genera. The pharmacophylogenetic analysis, integrated with therapeutic information, agreed with the taxonomy proposed previously, in which the family Ranunculaceae was divided into five sub-families: Ranunculoideae, Thalictroideae, Coptidoideae, Hydrastidoideae, and Glaucidioideae. It was plausible to organize the sub-family Ranunculoideae into ten tribes. The chemical constituents and therapeutic efficacy of each taxonomic group were reviewed, revealing the underlying connections between phylogeny, chemical diversity, and clinical use, which should facilitate the conservation and sustainable utilization of the pharmaceutical resources derived from the Ranunculaceae.


Assuntos
Alcaloides/análise , Biodiversidade , Filogenia , Extratos Vegetais/química , Ranunculaceae/química , Saponinas/análise , Terpenos/análise , Alcaloides/uso terapêutico , Aporfinas/análise , Aporfinas/uso terapêutico , Furanos/análise , Humanos , Metilglicosídeos/análise , Fitoterapia , Extratos Vegetais/uso terapêutico , Plantas Medicinais/química , Saponinas/uso terapêutico , Terpenos/uso terapêutico
12.
J Nanobiotechnology ; 13: 17, 2015 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-25889600

RESUMO

BACKGROUND: Cholangiocarcinoma (CC) is one of the fatal malignant neoplasms with poor prognosis. The traditional chemotherapy has been resistant to CC and does not improve the quality of life. The aim of the present study is to investigate the potential of chondroitin sulphate (CS)-histamine (HS) block copolymer micelles to improve the chemotherapeutic efficacy of docetaxel (DTX). RESULTS: pH-responsive property of CS-HS micelles was utilized to achieve maximum therapeutic efficacy in CC. In the present study, docetaxel-loaded CS-HS micelles (CSH-DTX) controlled the release of drug in the basic pH while rapidly released its cargo in the tumor pH (pH 5 and 6.8) possibly due to the breakdown of polymeric micelles. A nanosize of <150 nm will allow its accumulation in the tumor interstitial spaces via EPR effect. CSH-DTX effectively killed the cancer kills in a time- and concentration-dependent manner and showed pronounced therapeutic action than that of free drug at all-time points. CSH-DTX resulted in higher apoptosis of cancer cells with ~30% and ~50 of cells in early apoptosis quadrant when treated with 100 and 1000 ng/ml of equivalent drug. The micellar formulations showed remarkable effect in controlling the tumor growth and reduced the overall tumor volume to 1/5(th) to that of control and half to that of free drug treated group with no sign of drug-related adverse effects. Immunohistochemical analysis of tumor sections showed that fewer number of Ki-67 cells were present in CSH-DTX treated group comparing to that of free DTX treated group. CONCLUSION: Our data suggests that nanoformulation of DTX could potentially improve the chemotherapy treatment in cholangiocarcinoma as well as in other malignancies.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Nanocompostos/química , Taxoides/administração & dosagem , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral/efeitos dos fármacos , Colangiocarcinoma/patologia , Sulfatos de Condroitina/química , Preparações de Ação Retardada/química , Docetaxel , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Histamina/química , Humanos , Concentração de Íons de Hidrogênio , Camundongos Nus , Micelas , Nanocompostos/administração & dosagem , Taxoides/química , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Exp Ther Med ; 9(3): 829-834, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25667636

RESUMO

Cryptogenic organizing pneumonia (COP) is a pulmonary disorder associated with nonspecific clinical presentations. The macrolide class of antimicrobial agents is widely used to treat infectious and inflammatory respiratory diseases in humans. The present study reports a case of COP that was effectively treated with azithromycin in combination with glucocorticoid. A literature review of similar cases is also presented. It was found that all COP patients in the literature received macrolide treatment, including six cases with unknown clinical outcomes. For the remaining 29 patients, 20 patients initially received the macrolide as a single therapy and 4/5 of them (16 cases) were cured with a treatment time of 3-14 months, while 1/5 (4 cases) showed no improvement after treatment for 1 month and were switched to a glucocorticoid or combination treatment with a glucocorticoid, after which the disease was finally well-controlled. Side-effects of macrolide were rare. Based on this analysis, it is recommended that macrolides can be used as a first-line therapy in patients with mild COP. For patients with recurrent COP, it is suggested that macrolides should be used as an adjunctive therapy with other treatments, such as a glucocorticoid.

14.
Exp Ther Med ; 7(2): 443-446, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24396422

RESUMO

The present study aimed to evaluate whether circulating C-reactive protein (CRP) levels are a biomarker of systemic inflammation and a significant predictor of future chronic obstructive pulmonary disease (COPD) outcome. During the study, 116 patients with stable COPD and 35 age- and gender-matched healthy subjects with normal pulmonary function were observed. Patient follow-up was also performed to evaluate the strength of the associations between CRP levels and future outcomes. The observations from the present study showed that serum CRP levels were significantly higher in stable COPD patients than in control subjects (4.48±0.83 vs. 1.01±0.27 mg/l, respectively; P<0.05). In addition, it was identified that a serum CRP concentration of >3 mg/l is a poor prognostic variable of COPD compared with a CRP concentration of ≤3 mg/l [hazard ratio (HR), 2.71; 95% confidence interval (CI), 1.05-6.99; P<0.05]. A quantitative synthesis of four studies including 1,750 COPD patients was performed and statistically similar results were obtained (HR, 1.54; 95% CI, 1.14-2.07; P<0.01). The present study showed that circulating CRP levels are higher in stable COPD patients and, therefore, may be used as a long-term predictor of future outcomes. These observations highlight the importance of high sensitivity CRP assays in patients with stable COPD.

15.
Tumour Biol ; 35(3): 1805-11, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24146275

RESUMO

UNLABELLED: Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis in the process of tumor growth and metastasis. In present study, we conducted a case-control study and meta-analysis to evaluate the genetic effects of VEGF -634G/C and VEGF -2578C/A polymorphisms and risk of lung cancer. A total of 175 subjects were recruited for case-control study and seven studies were included in the meta-analysis. Our case-control study showed that VEGF -634G/C polymorphism had no association with lung cancer risk (CC vs. GG: OR = 0.88, 95% CI = 0.37-2.11), whereas there was an association between VEGF -2578CC genotype and decrease in lung cancer risk (CC vs. CA/AA: OR = 0.52, 95% CI = 0.28-0.96). A meta-analysis was further performed and statistically similar results were obtained (CC vs. GG: OR = 0.91, 95% CI = 0.60-1.39 for VEGF -634; CC vs. AA: OR = 0.53, 95% CI = 0.32-0.89 for VEGF -2578). Our study showed that the variant genotypes of the VEGF -2578C/A polymorphism, but not the VEGF -634G/C polymorphism, was associated with lung cancer risk. More studies are needed to detect VEGF -634G/C and VEGF -2578 polymorphisms and their association with lung cancer in different ethnic populations incorporated with environmental exposures.


Assuntos
Carcinoma/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Fator A de Crescimento do Endotélio Vascular/genética , Fator C de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Fatores de Risco
16.
Zhonghua Gan Zang Bing Za Zhi ; 20(2): 98-102, 2012 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-22464779

RESUMO

To investigate the efficacy of 104 weeks of lamivudine (LAM) and adefovir (ADV) de novo combination therapy, as compared to optimized combination therapy administered after 48 weeks of treatment with lamivudine or adefovir mono-therapy, in chronic hepatitis B (CHB) patients. A total of 174 patients with CHB were equally divided among three treatment groups: LAM mono-therapy; ADV mono-therapy; and LAM + ADV combination therapy. The patients in the LAM + ADV group were treated with LAM plus ADV for 104 consecutive weeks. The patients in the LAM or the ADV groups were first treated for 48 weeks with LAM or ADV, respectively, after which the patient's virological response was assessed. According to the results, the patient was continued on mono-therapy or switched to combination therapy for the subsequent 56 weeks. Virological and biochemical examinations were carried out at weeks 48 and 104. The rates of undetectable HBV DNA in the LAM mono-therapy, ADV mono-therapy, and LAM-ADV combination therapy groups at week 48 were 68%, 50%, and 84%, and at week 104 were 80%, 72%, and 95%, respectively. For the same groups, the virus breakthrough rates at week 48 were 15%, 0%, and 0%, and at week 104 were 18%, 2%, and 0%, respectively. Statistical analysis showed significant differences for the rate of undetectable HBV DNA between LAM + ADV group and LAM group at week 48 (x2 = 4.473, P= 0.034) and at week 104 (x2 = 5.795, P = 0.016), LAM + ADV group and ADM group at week 48 (x2 = 14.802, P less than 0.001) and week 104 (x2 = 5.547, P = 0.001). The hepatitis B e antigen (HBeAg) seroconversion rates at week 48 were 15% (x2 = 4.543, P = 0.033), 13% (x2 = 4.035, P = 0.045) and 38%, and at week 104 were 21% (x2 = 4.438, P = 0.035), 17% (x2 = 4.223, P = 0.04) and 44%, respectively, among patients positive for HBeAg. Statistical analysis showed that the differences among the three groups for each of these parameters were statistically significant (all, P less than 0.05). When compared with LAM or ADV mono-therapy followed by LAM+ADV at week 48, the LAM plus ADV de novo combination therapy for 104 weeks provided CHB patients with better virological and serological responses and a lower drug resistance rate.


Assuntos
Adenina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Lamivudina/administração & dosagem , Organofosfonatos/administração & dosagem , Adenina/administração & dosagem , Adenina/uso terapêutico , Adulto , Quimioterapia Combinada , Feminino , Humanos , Lamivudina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Organofosfonatos/uso terapêutico , Estudos Prospectivos , Resultado do Tratamento
17.
Chin Med J (Engl) ; 124(14): 2203-8, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21933627

RESUMO

BACKGROUND: Several studies have evaluated the association between polymorphisms of encoding excision repair cross complementation group 1 (ERCC1) enzyme and lung cancer risk in diverse populations but with conflicting results. By pooling the relatively small samples in each study, it is possible to perform a meta-analysis of the evidence by rigorous methods. METHODS: Embase, Ovid, Medline and Chinese National Knowledge Infrastructure were searched. Additional studies were identified from references in original studies or review articles. Articles meeting the inclusion criteria were reviewed systematically, and the reported data were aggregated using the statistical techniques of meta-analysis. RESULTS: We found 3810 cases with lung cancer and 4332 controls from seven eligible studies. T19007C polymorphism showed no significant effect on lung cancer risk (C allele vs. T allele: odds ratio (OR) = 0.91, 95% confidence interval (CI) = 0.80 - 1.04; CC vs. TT: OR = 0.76, 95%CI = 0.56 - 1.02; CC vs. (CT + TT): OR = 0.96, 95%CI = 0.84 - 1.10). Similarly, there was no significant main effects for T19007C polymorphism on lung cancer risk when stratified analyses by ethnicity (Chinese or Caucasian). No significant association was found between C8092A polymorphism (3060 patients and 2729 controls) and the risk of lung cancer (A allele vs. C allele: OR = 1.03, 95%CI = 0.95 - 1.11; AA vs. CC: OR = 1.08, 95%CI = 0.88 - 1.33; AA vs. (AC + CC): OR = 1.08, 95%CI = 0.88 - 1.31). CONCLUSION: We found little evidence of an association between the T1900C or C8092A polymorphisms of ERCC 1 and the risk of lung cancer in Caucasian or Han Chinese people.


Assuntos
Proteínas de Ligação a DNA/genética , Endonucleases/genética , Neoplasias Pulmonares/genética , Polimorfismo Genético/genética , Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença/genética , Humanos
18.
Med Oncol ; 28(4): 1169-75, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20635170

RESUMO

Published data on the association between vascular endothelial growth factor (VEGF) -2578C/A polymorphism and cancer risk is inconclusive. To derive a more precise estimation of association between VEGF -2578C/A polymorphism and the risk of cancer, we performed a meta-analysis of 5415 cancer cases and 5848 controls from 16 published case-control studies. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. Our meta-analysis indicated that VEGF -2578C/A polymorphism was associated with the risk of colorectal cancer under homozygote comparison (OR=0.70, 95% CI=0.53-0.92), dominant model (OR=0.72, 95% CI=0.57-0.92), and recessive model (OR=0.82, 95% CI=0.67-1.01), although no evidence of association between VEGF -2578C/A polymorphism and cancer risk was observed as we compared in the pooled analyses (homozygote comparison: OR=0.97, 95% CI=0.81-1.16). More studies are needed to detect VEGF -2578C/A polymorphism and its association with cancer in different ethnic populations incorporated with environmental exposures in the susceptibility of different kinds of cancer.


Assuntos
Predisposição Genética para Doença , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Fator A de Crescimento do Endotélio Vascular/genética , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Fatores de Risco
19.
Arch Med Res ; 41(7): 548-57, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21167395

RESUMO

BACKGROUND AND AIMS: A number of investigators have studied the possible association between vascular endothelial growth factor (VEGF) polymorphisms and cancer risk, but the results have been conflicting. To examine the risk of cancer associated with the +936C/T and +405G/C polymorphisms of VEGF, all available studies were considered in the present meta-analysis. METHODS: We performed a computerized search of PubMed and Embase database for relevant studies. Articles meeting the inclusion criteria were reviewed systematically, and the reported data were aggregated using the statistical techniques of meta-analysis. RESULTS: Overall, the 936C allele showed no significant effect on cancer risk compared with the 936T allele in all subjects (OR = 0.77, 95% CI = 0.53-1.14; random model). Similarly, no significant effect of 405G allele compared with 405C on cancer risk was found (OR = 1.08, 95% CI = 0.94-1.24; random model). It indicated that the VEGF +936C/T and +405G/C polymorphisms might not be risk factors for cancer, but the 936C allele was associated with a decreased risk of oral cancer (OR = 0.72, 95% CI = 0.53-0.97; fixed model). CONCLUSIONS: The evidence from our meta-analysis supports that there was an association between 936C allele and decreased oral cancer risk, although no evidence of association between VEGF +936C/T or +405G/C polymorphism and cancer was observed in all examined patients. Further studies based on larger, stratified population are required to explore the role of VEGF polymorphisms on cancer risk.


Assuntos
Neoplasias/genética , Polimorfismo Genético , Fator A de Crescimento do Endotélio Vascular/genética , Alelos , Humanos , PubMed , Fatores de Risco
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