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1.
Brain Res ; 1829: 148845, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38452845

RESUMO

Formononetin has been demonstrated to protect against cerebral ischemia-reperfusion injury, however its mechanism has to be further researched. This study examined the effect of formononetin on cerebral ischemia-reperfusion injury in rats using the PARP-1/PARG/Iduna signaling pathway. In male SD rats, a model of cerebral ischemia-reperfusion injury was developed. Animals were randomly assigned to one of eight groups: Sham operation, Sham operation + formononetin, MCAO, MCAO + formononetin, PARP inhibitor (PJ34) + MCAO, formononetin + PJ34 + MCAO, PARG inhibitor (Ethacridine lactate) + MCAO, and ethacridine lactate + formononetin. The neurological deficit test, TTC staining, HE staining, Nissl staining, TUNEL staining, and western blotting were utilized to assess formononetin's protective effects in MCAO rats. The data show that formononetin can effectively alleviate neurological dysfunction and pathological changes in brain tissue in rats with cerebral ischemia-reperfusion injury, reduce the area of cerebral infarction and neuronal apoptosis, decrease the protein levels of PARP-1, PARG, Caspase-3, P53, and AIF in brain tissue, and increase the protein levels of Iduna and p-AKT. As a result, we concluded that formononetin improves brain ischemia-reperfusion injury in rats by modulating the PARP-1/PARG/Iduna signaling pathway.


Assuntos
Isquemia Encefálica , Isoflavonas , Fenantrenos , Traumatismo por Reperfusão , Ratos , Animais , Masculino , Ratos Sprague-Dawley , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Etacridina/farmacologia , Etacridina/uso terapêutico , Transdução de Sinais , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo
2.
New Microbiol ; 46(4): 361-366, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38252047

RESUMO

The in vitro antimicrobial activity of the active ingredient in antimicrobial magistral drug formulations and plant extracts used in folk medicine were investigated comparatively. Borax, sulfur colloid, hydrogen peroxide, benzoic acid, rivanol, brilliant green and plant extracts as active ingredients, namely: Helianthus tuberosus tuber-H2O (aqueous extract), Cydonia oblonga leaves-H2O, Allium porrum whole plant-H2O, Cistus laurifolius leaves-EtOH, Solanum muricalum-H2O, and Fumaria cilicica leaves-EtOH were studied to determine their antimicrobial activity against different bacteria and fungi (S. pyogenes, S. aureus, S. epidermidis, E. faecalis, K. pneumonia, H. influenza, P. aeruginosa, A. baumannii, E. coli, Candida albicans, C. tropicalis, C. parapsilosis, C. krusei) by using the microdilution method. The active ingredients and plant extracts showed different activities as MIC between 1->128 µg/mL. Brilliant green and rivanol as active ingredients had MIC values of 1 µg/mL against all tested microorganisms. C. oblonga leaves-H2O as well as C. laurifolius leaves-EtOH as plant extracts were indicated as having the highest antimicrobial effect in MIC value of 16 µg/ml against A. baumannii and S. pyogenes, respectively. On the other hand, F. cilicica leaves-EtOH and C. laurifolius leaves-EtOH showed the highest antifungal activity (MIC; 16 µg/mL).


Assuntos
Anti-Infecciosos , Plantas Medicinais , Compostos de Amônio Quaternário , Humanos , Etacridina , Escherichia coli , Staphylococcus aureus , Anti-Infecciosos/farmacologia , Etanol , Extratos Vegetais/farmacologia
3.
J Matern Fetal Neonatal Med ; 36(2): 2249187, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37654101

RESUMO

OBJECTIVE: To explore the suitable regimens of induced termination of second-trimester pregnancy in women with prior cesareans. METHODS: A total of 204 s-trimester pregnant women with prior cesareans at the Third Affiliated Hospital of Zhengzhou University from January 2019 to December 2020 were included in this retrospective study. Group A included pregnant women who were administered mifepristone with misoprostol, Group B included those administering mifepristone with misoprostol as well as a transcervical Cook double-balloon catheter, Group C included those receiving mifepristone with an intra-amniotic injection of ethacridine lactate, and Group D included those receiving mifepristone, transcervical Cook double-balloon catheter, and intra-amniotic injection of ethacridine lactate. Their characteristics, clinical outcomes, and complications among the four groups were compared. RESULTS: All women had similar profiles in maternal age, gravidity, and previous cesarean delivery (p > .05). There was no significant difference in successful abortion among the four groups (p > .05). Group C had a significantly shorter induction-to-abortion interval than Group D (p < .01). The blood loss after abortion at 2 h in Group B was much less than Group A (p < .05). It made a significant difference between Group B and Group D regarding the blood loss after abortion at 2 h (p < .01). With regard to total incidences of adverse reactions, there were much fewer in the group B than the group A (p < .05). CONCLUSION: The four regimens are all effective for the termination of second-trimester pregnancy in women with prior cesareans. The use of transcervical Cook double-balloon could reduce the risks caused by misoprostol, and the combination of these is feasible to induce second-trimester pregnancy termination in women with prior cesareans.


Assuntos
Cesárea , Misoprostol , Gravidez , Feminino , Humanos , Segundo Trimestre da Gravidez , Etacridina , Mifepristona , Estudos Retrospectivos
4.
Asian J Endosc Surg ; 16(1): 143-146, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35778988

RESUMO

We previously reported that probe-based confocal laser endomicroscopy using acrinol can depict cancerous nuclei. The objective of this study was to confirm the safety of acrinol in patients. For all seven patients, '50 ml' of a 0.1% acrinol and '1 ml' of 10% fluorescein in 99 ml of normal saline were introduced into the bladder. The laser probe adhered to the suspicious lesion from the working channel of the cystoscope. The patients underwent mucosal biopsy and transurethral resection after observation. Adverse events were noted during a valuation using common terminology criteria for adverse events version 4.0. Confocal laser endomicroscopy detected the nuclei of cancer cells in all seven patients. No adverse event was observed in any of the seven patients. Confocal laser endomicroscopy using acrinol as a novel dye can help visualize the cancerous nuclei of bladder urothelial carcinoma during cystoscopy without severe adverse events.


Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/cirurgia , Carcinoma de Células de Transição/patologia , Etacridina , Ressecção Transuretral de Bexiga , Microscopia Confocal , Cistoscopia , Lasers
5.
BMC Pregnancy Childbirth ; 22(1): 790, 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36289479

RESUMO

OBJECTIVE: To review and analyze the efficacy and safety of mifepristone combined with ethacridine lactate for induction of stillbirth in the third trimester. METHODS: All patients with stillbirth in late pregnancy (≥ 28 weeks) in a university-affiliated maternity center from October 2016 to September 2021 were included in this study. After exclusion, patients were divided into ethacridine lactate and non-ethacridine lactate groups according to induction methods. Logistic regression was conducted to identify the risks of complications. RESULTS: We identified 122 patients that experienced stillbirth (5' Apgar score = 0) in third-trimester from the 5-year total deliveries in the hospital, among whom 39 stillbirths that resulted from termination of pregnancy for severe fetal anomalies and 1 stillbirth that was in twin pregnancy were excluded. Thus, 82 cases with stillbirths (dead before induction) were included in the analyses. In the 82 cases, 49 (59.76%) accepted intra-amniotic ethacridine lactate induction with 47 (95.92%, 47/49) successfully induced. No statistical difference was observed in induction failure rate between ethacridine dosage groups of < 75mg and ≥ 75mg (0/25, vs. 2/24, respectively; P > 0.05). The ethacridine lactate induction group showed no increased risks in complications (6.12%, 3/49), compared with non-ethacridine lactate group (12.12%, 4/33) (P = 0.35, OR, 0.47, 95%CI, 0.10 to 2.27). CONCLUSION: Mifepristone combined with ethacridine lactate is a safe and low-risk induction method for patients with stillbirth in the third trimester.


Assuntos
Aborto Induzido , Mifepristona , Humanos , Feminino , Gravidez , Mifepristona/efeitos adversos , Etacridina/efeitos adversos , Terceiro Trimestre da Gravidez , Natimorto/epidemiologia , Aborto Induzido/métodos , Segundo Trimestre da Gravidez , China/epidemiologia , Lactatos
6.
Medicine (Baltimore) ; 101(38): e30767, 2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36197253

RESUMO

BACKGROUND: Second-trimester induced labor in pregnant women was often more likely to suffer from psychological and physiological double pain. However, the analgesic management received less attention, and the optimal analgesic mode for second-trimester induced labor had not been determined. Our objective was to evaluate the feasible of epidural analgesia (EA) in second-trimester induced labor. METHODS: From January 2020 to December 2021, Primipara who planned to undergo second-trimester induced labor in the First Affiliated Hospital of Yangtze University were collected. The method of labor induction was oral mifepristone + amniotic cavity injection of Ethacridine Lactate. Based on whether or not patients received epidural analgesia, which were divided into EA group (30 cases) and non-EA (NEA) group (30 cases). The primary outcome were visual analog scale (VAS) score of pain and result of follow-up, the secondary outcomes included relative clinical parameter and labor duration. RESULTS: Vaginal induction of labor was successful in both groups. There was no statistically significant difference in VAS of pain between the two groups before analgesia (P > .05), but the VAS of pain in the EA group was significantly lower than the NEA group (P < .05) after analgesia or at delivery. The following outcomes showed no statistical difference between two groups: labor duration, postpartum hemorrhage, hemorrhage ≥ 500 mL, intrapartum injury, second days hemoglobin, C-reactive protein, antibiotic therapy days, hospitalizations days, and placenta residue (P > .05). The median hospitalization costs of EA group was 4697.5 yuan, and NEA group was 3673 yuan, the difference was statistically significant (P < .001). No adverse events related to EA occurred during hospitalization, only 3 patients showed mild lumbago and back pain after follow-up to three months postpartum, which was significantly relieved after proper rest. CONCLUSION: EA can significantly reduce the pain of parturients, which may be effective and safe in the second-trimester induced labor.


Assuntos
Analgesia Epidural , Analgesia Obstétrica , Trabalho de Parto , Analgesia Epidural/efeitos adversos , Analgesia Epidural/métodos , Analgesia Obstétrica/efeitos adversos , Analgesia Obstétrica/métodos , Analgésicos/farmacologia , Antibacterianos/farmacologia , Proteína C-Reativa , Etacridina/farmacologia , Feminino , Humanos , Trabalho de Parto Induzido , Mifepristona , Dor/etiologia , Gravidez , Segundo Trimestre da Gravidez , Estudos Prospectivos
7.
Medicine (Baltimore) ; 101(31): e29908, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35945718

RESUMO

BACKGROUND: Prenatal bleeding is very dangerous for pregnant women with placenta previa during termination of pregnancy in the mid-trimester. Traditionally, cesarean section or hysterectomy is used to stop bleeding. This study aims to investigate the method for termination of mid-trimester pregnancy with placenta previa, especially emergency uterine artery embolization (UAE) combined with cervical double balloon (CDB). METHODS: A retrospective study was conducted based on 261 cases of mid-pregnancy termination in our hospital, where 34 cases with placenta previa were set as the observation group, and the remaining 227 cases were set as control group. At first, the termination method of Mifepristone combined with Misoprostol/Ethacridine Lactate was adopted. If the volume of prenatal bleeding was up to 400 mL, emergency uterine artery embolization (UAE) was implemented to stop bleeding, then cervical double balloon (CDB) was used to promote cervical ripening. Receiver operating characteristic (ROC) curves analysis was performed to assess the accuracy in predicting the length of placental edge crossed the cervical os for prenatal bleeding. RESULTS: The number of gravidity/parities, the rate of cesarean section, the medical cost, the rate of previous cesarean section were all higher in the observation group than in the control group (P < .05). The volume of prenatal hemorrhage, postpartum hemorrhage, the rate of puerperal morbidity, emergency UAE rate and ICU rate were higher in the observation group than in the control group (P < .05). There were 4 cases showing prenatal hemorrhage up to 400 mL and undergoing emergency UAE + CDB in the observation group, while there were no such cases in the control group (P < .05). An optimal cut-off value of 1.7cm for the length of placental edge crossed the cervical os in diagnosing prenatal hemorrhage demonstrated sensitivity and specificity of 75.0% and 86.7%, respectively (area under the ROC curve, 0.858). CONCLUSION: The combined therapy of mifepristone and Misoprostol/Ethacridine Lactate was useful for termination of mid-trimester pregnancy with placenta previa, and attention needs to be attached to prenatal hemorrhage during labor induction. Emergency UAE + CDB is a good combination method to treat prenatal hemorrhage and promote cervical ripening during the induction.


Assuntos
Misoprostol , Placenta Prévia , Cesárea , Etacridina , Feminino , Humanos , Mifepristona , Placenta , Placenta Prévia/terapia , Gravidez , Estudos Retrospectivos
8.
PLoS Pathog ; 17(9): e1009898, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34478458

RESUMO

The respiratory disease COVID-19 is caused by the coronavirus SARS-CoV-2. Here we report the discovery of ethacridine as a potent drug against SARS-CoV-2 (EC50 ~ 0.08 µM). Ethacridine was identified via high-throughput screening of an FDA-approved drug library in living cells using a fluorescence assay. Plaque assays, RT-PCR and immunofluorescence imaging at various stages of viral infection demonstrate that the main mode of action of ethacridine is through inactivation of viral particles, preventing their binding to the host cells. Consistently, ethacridine is effective in various cell types, including primary human nasal epithelial cells that are cultured in an air-liquid interface. Taken together, our work identifies a promising, potent, and new use of the old drug via a distinct mode of action for inhibiting SARS-CoV-2.


Assuntos
Antivirais/farmacologia , Etacridina/farmacologia , Inibidores de Proteases/farmacologia , Ativação Viral/efeitos dos fármacos , Animais , Linhagem Celular , Chlorocebus aethiops , Proteases 3C de Coronavírus/antagonistas & inibidores , Genes Reporter , Proteínas de Fluorescência Verde/genética , Humanos , Células Vero , Vírion/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
9.
Zhonghua Fu Chan Ke Za Zhi ; 56(6): 418-424, 2021 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-34154317

RESUMO

Objective: To study the risk assessment, method selection and clinical management of pregnancy termination during the first and second trimester of pregnant women with cardiovascular disease. Methods: This study focused on pregnant women with cardiovascular diseases who were admitted to Beijing Anzhen Hospital during the first and second trimester of pregnancy from January 2016 to September 2019, to summarize their clinical characteristics, reasons and methods of pregnancy termination, management and outcomes. Results: Among 167 pregnant women, 119 cases (71.3%, 119/167) were in early pregnancy and 48 cases (28.7%, 48/167) were in middle pregnancy. The reasons for termination of pregnancy were cardiovascular disease (109 cases; 65.3%, 109/167), unwanted pregnancy (54 cases; 32.3%, 54/167) and other reasons (4 cases). Vacuum aspiration was performed in 98 cases and forceps curettage was performed in 19 cases, medical abortion was performed in 2 cases in early pregnancy. There was no change in cardiac function after pregnancy termination and all survived in early pregnancy. In the second trimester, 16 cases were induced by intraamniotic injection of ethacridine, 2 cases by water balloon, 1 case by oxytocin intravenous drip, and 29 cases by hysterotomy delivery. The ratio of patients with hysterotomy delivery with cardiac function grade Ⅲ-Ⅳ was significantly higher than that in the patients with vaginal labor induction in the second trimester [79% (23/29) vs 4/19; P<0.01]; the ratio of pregnancy risk grade Ⅳ-Ⅴ was also significantly higher [100% (29/29) vs 14/19; P=0.007]. The mean length of hospital stay of patients with hysterotomy delivery was significantly longer than that in the patients with vaginal labor induction [(7.1±3.4) vs (2.4±1.8) days; P<0.01]. Cardiac function was improved in 4 patients induced by ethacridine and rapid recovery without serious complications. Cardiac function decreased in 5 cases and 1 case died on the first day after hysterotomy delivery. Conclusions: Pregnancy risk assessment should be conducted as early as possible in patients with cardiovascular disease. If it is not suitable to continue the pregnancy, terminate pregnancy as early as possible to reduce the risk. Pregnancy termination methods and analgesic methods should be selected according to different gestational age and complications. The indications for hysterotomy delivery should not be relaxed at will, so as to minimize trauma and hemodynamic changes. After the termination of pregnancy, contraceptive measures should be implemented and the next treatment plan should be guided.


Assuntos
Aborto Induzido , Doenças Cardiovasculares , Etacridina , Feminino , Humanos , Gravidez , Primeiro Trimestre da Gravidez , Segundo Trimestre da Gravidez , Gestantes
10.
Acta Bioeng Biomech ; 22(2): 185-197, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32868952

RESUMO

PURPOSE: The polymeric porous surface of fibres (PLA) may influence the kinetics of release of biologically active compounds (gentamicin, G and ethacridine lactate, R) affecting development of a bacterial biofilm. METHODS: The porous fibres with different morphology were manufactured by the electrospinning method from ternary systems composed of PLA and selected solvents. Fibres morphology was examined using a scanning electron microscopy (SEM), their structure was analyzed by FT-IR ATR spectroscopy and differential scanning calorimetry (DSC). Changes in the drug release profile were measured using ICP/UV-Vis methods and the resulting bactericidal or bacteriostatic properties were tested by two-layer disk diffusion test in relation to various drug incorporation methods. RESULTS: The porous fibres can be applied to produce drug-bearing membranes. The spectroscopic studies confirmed incorporation of gentamicin into the fibres and the presence of ethacridine lactate on their surface. Bimodal fibres distribution (P3) promoted faster release of gentamicin and ethacridine lactate from P3G and P3R materials. The electrospinning process coupled with the vapor induced phase separation influenced the glass transition temperature of the porous polymer fibres. The pre/post-electrospinning modification influenced the glass transition, maximum temperature of cold crystallization and melting point of the porous membrane, compared to the neat polymer. The polylactide fibres with gentamicin showed strong bactericidal effect on Gram-positive bacteria, while fibres with ethacridine lactate were bacteriostatic. CONCLUSIONS: The obtained fibres with complex surface morphology can be used as a membrane in active dressings as they make it possible to control the release profile of the active compounds.


Assuntos
Bandagens , Portadores de Fármacos/química , Poliésteres/química , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/ultraestrutura , Etacridina/farmacologia , Gentamicinas/química , Gentamicinas/farmacologia , Testes de Sensibilidade Microbiana , Porosidade , Soluções , Espectrometria por Raios X , Espectroscopia de Infravermelho com Transformada de Fourier , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus aureus/ultraestrutura
11.
Zhonghua Bing Li Xue Za Zhi ; 49(8): 782-787, 2020 Aug 08.
Artigo em Chinês | MEDLINE | ID: mdl-32746543

RESUMO

Objective: Placental pathology reflects the health condition of both mother and fetus during pregnancy, providing information about pathogenesis especially in adverse pregnancies, and may provide guidance on subsequent pregnancies. Description on the placental changes after long-term use of rivanol is lacking, and this evaluated the placental changes, with emphasis on the differential diagnosis from other primary placental lesions. Methods: A total of 85 placentas from rivanol induced abortion submitted to the Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University from Januaury 2017 to October 2019 were reviewed; and 81 gestational-age-matched cases of spontaneous abortion or preterm delivery during the same period were also included as the control group. Diagnoses were based on the consensus statement of 2016 Amsterdam Placental Workshop Group. Statistical differences were analyzed by individual diagnostic terms. Results: The maternal age in rivanol group was (30.5±4.1) (range 22-41) years, compared with (30.9±4.3) (range 22-44) years in the control group. Gestational age was (23.2±3.5) (range 17-35) weeks and (23.3±2.8) (range 17-33) weeks in the rivanol and control groups. The incidence of chorioamnionitis in rivanol group was 91.8%, significantly higher than the control (63.0%, P<0.05); and there were more stage 1 (subchorionic) maternal response in rivanol than in the control (61.0% vs.28.6%, P<0.05) groups. In addition, acute deciduitis was also more common in rivanol group (27.1% vs. 13.6%, P<0.05). No significant difference was observed in fetal inflammatory responses (vasculitis of vessels in chorion plate and umbilical cord); maternal malperfusion (narrowing of intervillous space, increased intervillous fibrin deposition, decidual arteriopathy, villous infarction and retroplacental hematoma); and fetal malperfusion (villous stromal hemorrhage and avascular villi). Conclusions: The chemical chorioamnionitis caused by rivanol is characterized by maternal inflammatory response of low stage and high grade. The use of rivanol has no obvious impact on the fetal inflammatory response, maternal malperfusion and fetal malperfusion. Such morphologic changes may reflect the original placental lesions.


Assuntos
Aborto Induzido , Corioamnionite , Etacridina , Nascimento Prematuro , Feminino , Humanos , Recém-Nascido , Placenta , Gravidez
12.
J Int Med Res ; 48(7): 300060520933811, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32643981

RESUMO

Impetigo herpetiformis is a rare variant of generalized pustular psoriasis that occurs during pregnancy or is triggered by pregnancy, often in association with hypocalcemia. This condition is associated with increased maternal and fetal morbidity and mortality. We report a 29-year-old pregnant woman who presented to hospital at the gestational age of 20 weeks with widespread erythema covered with pustules that coalesced to form lakes of pus. She did not respond to corticosteroids, immunosuppressants, or phototherapy. Finally, intra-amniotic injection of ethacridine lactate was administered to terminate the pregnancy, and the patient showed complete recovery in 3 months. Insight from this case report may facilitate optimal management of this relatively rare entity.


Assuntos
Impetigo/complicações , Impetigo/mortalidade , Impetigo/terapia , Aborto Induzido/métodos , Corticosteroides , Adulto , China , Etacridina/farmacologia , Feminino , Humanos , Imunossupressores , Gravidez , Psoríase/complicações
13.
Thyroid ; 30(11): 1666-1675, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32345138

RESUMO

Objective: It has been demonstrated that the transcription factors TAZ (transcriptional coactivator with PDZ-binding motif), paired box gene 8 (PAX8), and NK2 homeobox 1 (NKX2-1) are coexpressed in the nucleus of thyroid cells. Furthermore, TAZ is known to enhance the transcriptional activity of PAX8 and NKX2-1 as well as the key thyroid-specific gene, thyroglobulin (TG), suggesting a critical role for TAZ in the control of thyroid cell speciation. We previously reported that the small molecule ethacridine, identified as a TAZ activator, was able to induce thyroid-specific transcription in endodermal cells differentiated from human embryonic stem (hES) cells using activin A. Since transcription factors are epigenetically regulated in cell differentiation, we investigated the epigenetic changes in the promoter regions of these key transcription factors during in vitro differentiation of hES cells into thyrocytes. Methods: We initially profiled chromatin accessibility using the technique of Assay for Transposase Accessible Chromatin sequencing (ATAC-seq), and then examined DNA methylation and histone acetylation in the promoter regions of the three selected thyroid transcription factors and the thyroid-specific genes during hES cell differentiation. Results: ATAC-seq analysis showed enriched chromatin accessibility of TAZ, NKX2-1, and PAX8 after exposure to activin A and ethacridine. There were no methylation changes found in the NKX2-1, PAX8, and TAZ promoters by bisulfite sequencing. In contrast, acetylation of histone H4, specifically acetylation of lysine 16, was observed in each of the promoters when measured by chromatin immunoprecipitation polymerase chain reaction assays, which correlated with the activity and expression of NKX2-1 and PAX8 as well as sodium/iodide symporter, thyroid stimulating hormone receptor, and TG genes. Conclusions: These results indicate that ethacridine treatment of activin A-derived endodermal hES cells leads to enhanced chromatin accessibility, which, in turn, allows histone H4 acetylation in the regulation of active genes for speciation of thyroid follicular cells from hES cells.


Assuntos
Diferenciação Celular , Metilação de DNA , Epigênese Genética , Glândula Tireoide/citologia , Glândula Tireoide/imunologia , Ativinas/metabolismo , Cromatina/química , Etacridina/farmacologia , Histonas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lisina , Fator de Transcrição PAX8/biossíntese , Fator de Transcrição PAX8/genética , Regiões Promotoras Genéticas , Análise de Sequência de DNA , Células Epiteliais da Tireoide/citologia , Fator Nuclear 1 de Tireoide/biossíntese , Fator Nuclear 1 de Tireoide/genética , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional
14.
Curr Drug Res Rev ; 11(2): 118-128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31513003

RESUMO

BACKGROUND: Human Epidermal development factor Receptor-2 (HER2) is a membrane tyrosine kinase which is overexpressed and gene amplified in human breast cancers. HER2 amplification and overexpression have been linked to important tumor cell proliferation and survival pathways for 20% of instances of breast cancer. 9-aminoacridines are significant DNA-intercalating agents because of their antiproliferative properties. OBJECTIVE: Some novel isoxazole substituted 9-anilinoacridines(1a-z) were designed by in-silico technique for their HER2 inhibitory activity. Docking investigations of compounds 1a-z are performed against HER2 (PDB id-3PP0) by using Schrodinger suit 2016-2. METHODS: Molecular docking study for the designed molecules 1a-z are performed by Glide module, in-silico ADMET screening by QikProp module and binding free energy by Prime-MMGBSA module of Schrodinger suit. The binding affinity of designed molecules 1a-z towards HER2 was chosen based on GLIDE score. RESULTS: Many compounds showed good hydrophobic communications and hydrogen bonding associations to hinder HER2. The compounds 1a-z, aside from 1z have significant Glide scores in the scope of - 4.91 to - 10.59 when compared with the standard Ethacridine (- 4.23) and Tamoxifen (- 3.78). The in-silico ADMET properties are inside the suggested about drug likeness. MM-GBSA binding of the most intense inhibitor is positive. CONCLUSION: The outcomes reveal that this study provides evidence for the consideration of isoxazole substituted 9-aminoacridine derivatives as potential HER2 inhibitors. The compounds, 1s,x,v,a,j,r with significant Glide scores may produce significant anti breast cancer activity and further in vitro and in vivo investigations may prove their therapeutic potential.


Assuntos
Amsacrina/análogos & derivados , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Isoxazóis/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Amsacrina/química , Amsacrina/farmacocinética , Amsacrina/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacocinética , Simulação por Computador , Desenho de Fármacos , Etacridina/farmacologia , Feminino , Humanos , Ligação de Hidrogênio , Isoxazóis/química , Isoxazóis/farmacocinética , Modelos Moleculares , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade , Tamoxifeno/farmacologia
15.
Anticancer Res ; 39(8): 4095-4100, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366493

RESUMO

BACKGROUND/AIM: Ethacridine is used as a topical antiseptic as well as for second-trimester abortion. Recent studies showed that ethacridine is an inhibitor of poly(ADP-ribose) glycohydrolase (PARG) and an activator of the transcriptional coactivator with PDZ-binding motif (TAZ). This study examined the effects of ethacridine on thyroid cancer cells. MATERIALS AND METHODS: Thyroid cancer cell lines (FTC133 and SW1736) and thyroid follicular epithelial cells (Nthy-ori 3-1) were treated with ethacridine. Viability, clonogenicity, cell-cycle distribution, and apoptosis were evaluated. The expression of thyroid differentiation markers (TTF-1, PAX8, and NIS) was determined by real-time PCR. RESULTS: Ethacridine suppressed cell growth and clonogenic ability of thyroid cancer cells in a time- and dose-dependent manner (p<0.001). No cell-cycle arrest was found, but ethacridine dose-dependently induced apoptosis of thyroid cancer cells (p<0.001). The PAX8 and NIS expressions were significantly increased in SW1736 (3.41-fold and 1.53-fold, respectively) and Nthy-ori 3-1 cells (2.73-fold and 4.12-fold, respectively). CONCLUSION: Ethacridine elicits apoptotic cell death in thyroid cancer cells and promotes differentiation in a subset of thyroid follicular cells.


Assuntos
Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Etacridina/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fator de Transcrição PAX8/genética , Simportadores/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Fator Nuclear 1 de Tireoide/genética
19.
Invest Ophthalmol Vis Sci ; 58(7): 3118-3126, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28632878

RESUMO

Purpose: GPR143 regulates melanosome biogenesis and organelle size in pigment cells. The mechanisms underlying receptor function remain unclear. G protein-coupled receptors (GPCRs) are excellent pharmacologic targets; thus, we developed and applied a screening approach to identify potential GPR143 ligands and chemical modulators. Methods: GPR143 interacts with ß-arrestin; we therefore established a ß-arrestin recruitment assay to screen for compounds that modulate activity. Because GPR143 is localized intracellularly, screening with the wild-type receptor would be restricted to agents absorbed by the cell. For the screen we used a mutant receptor, which shows similar basal activity as the wild type but traffics to the plasma membrane. We tested two compound libraries and investigated validated hits for their effects on melanocyte pigmentation. Results: GPR143, which showed high constitutive activity in the ß-arrestin assay, was inhibited by several compounds. The three validated inhibitors (pimozide, niclosamide, and ethacridine lactate) were assessed for impact on melanocytes. Pigmentation and expression of tyrosinase, a key melanogenic enzyme, were reduced by all compounds. Because GPR143 appears to be constitutively active, these compounds may turn off its activity. Conclusions: X-linked ocular albinism type I, characterized by developmental eye defects, results from GPR143 mutations. Identifying pharmacologic agents that modulate GPR143 activity will contribute significantly to our understanding of its function and provide novel tools with which to study GPCRs in melanocytes and retinal pigment epithelium. Pimozide, one of three GPR143 inhibitors identified in this study, maybe be a good lead structure for development of more potent compounds and provide a platform for design of novel therapeutic agents.


Assuntos
Albinismo Ocular/genética , Proteínas do Olho/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Glicoproteínas de Membrana/genética , Mutação , RNA/genética , Albinismo Ocular/tratamento farmacológico , Albinismo Ocular/metabolismo , Células Cultivadas , Análise Mutacional de DNA , Etacridina/farmacologia , Éxons , Proteínas do Olho/antagonistas & inibidores , Proteínas do Olho/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/dietoterapia , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Humanos , Ligantes , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/metabolismo , Niclosamida/farmacologia , Linhagem , Pimozida/farmacologia
20.
Thyroid ; 27(2): 292-299, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27829313

RESUMO

OBJECTIVE: The differentiation program for human thyroid follicular cells (TFCs) relies on the interplay between sequence-specific transcription factors and transcriptional co-regulators. Transcriptional co-activator with PDZ-binding motif (TAZ) is a co-activator that regulates several transcription factors, including PAX8 and NKX2-1, which play a central role in thyroid-specific gene transcription. TAZ and PAX8/NKX2-1 are co-expressed in the nuclei of thyroid cells, and TAZ interacts directly with both PAX8 and NKX2-1, leading to their enhanced transcriptional activity on the thyroglobulin (TG) promoter and additional genes. METHODS: The use of a small molecule, ethacridine, recently identified as a TAZ activator, in the differentiation of thyroid cells from human embryonic stem (hES) cells was studied. First, endodermal cells were derived from hES cells using Activin A, followed by induction of differentiation into thyroid cells directed by ethacridine and thyrotropin (TSH). RESULTS: The expression of TAZ was increased in the Activin A-derived endodermal cells by ethacridine in a dose-dependent manner and followed by increases in PAX8 and NKX2-1 when assessed by both quantitative polymerase chain reaction and immunostaining. Following further differentiation with the combination of ethacridine and TSH, the thyroid-specific genes TG, TPO, TSHR, and NIS were all induced in the differentiated hES cells. When these cells were cultured with extracellular matrix-coated dishes, thyroid follicle formation and abundant TG protein expression were observed. Furthermore, such hES cell-derived thyroid follicles showed a marked TSH-induced and dose-dependent increase in radioiodine uptake and protein-bound iodine accumulation. CONCLUSION: These data show that fully functional human thyroid cells can be derived from hES cells using ethacridine, a TAZ activator, which induces thyroid-specific gene expression and promotes thyroid cell differentiation from the hES cells. These studies again demonstrate the importance of transcriptional regulation in thyroid cell development. This approach also yields functional human thyrocytes, without any gene transfection or complex culture conditions, by directly manipulating the transcriptional machinery without interfering with intermediate signaling events.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Etacridina/farmacologia , Células-Tronco Embrionárias Humanas/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Células Epiteliais da Tireoide/efeitos dos fármacos , Tireotropina/farmacologia , Ativinas/farmacologia , Autoantígenos/efeitos dos fármacos , Autoantígenos/genética , Diferenciação Celular/genética , Células-Tronco Embrionárias Humanas/citologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Iodeto Peroxidase/efeitos dos fármacos , Iodeto Peroxidase/genética , Proteínas de Ligação ao Ferro/efeitos dos fármacos , Proteínas de Ligação ao Ferro/genética , Fator de Transcrição PAX8/efeitos dos fármacos , Fator de Transcrição PAX8/genética , Receptores da Tireotropina/efeitos dos fármacos , Receptores da Tireotropina/genética , Simportadores/efeitos dos fármacos , Simportadores/genética , Tireoglobulina/efeitos dos fármacos , Tireoglobulina/genética , Células Epiteliais da Tireoide/citologia , Fator Nuclear 1 de Tireoide/efeitos dos fármacos , Fator Nuclear 1 de Tireoide/genética , Transativadores , Fatores de Transcrição , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional
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