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1.
J Org Chem ; 86(22): 15886-15896, 2021 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33534572

RESUMO

Tunable electrocatalytic annulation reactions of o-arylalkynylanilines have been established, leading to green and divergent syntheses of skeletally diverse indoles by adjusting the electrolytes and the solvents. The presence of ammonium halides as the electrolytes enabled the halogenation of o-arylalkynylanilines to give C3-halogenated indoles whereas naphtho[1',2':4,5]furo[3,2-b]indoles could be obtained by changing the electrolyte from ammonium halides to KI. Interestingly, by combining acetone as the solvent and both NH4I and NH4Cl as the electrolytes, the reaction worked through an intramolecular annulation and [5 + 1] cyclization cascade to form naphtho[1',2':5,6][1,3]oxazino[3,4-a]indoles.


Assuntos
Halogenação , Indóis , Ciclização , Solventes
2.
J Int Med Res ; 48(11): 300060520964006, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33203273

RESUMO

OBJECTIVE: The study aimed to evaluate cervical ripening by measuring cervical collagen levels in non-pregnant women, women with a normal pregnancy, and postpartum women by light-induced fluorescence (LIF). METHODS: Cervical collagen content in normal pregnant women (n = 165) at various times of gestation was measured by LIF with a collascope, which is specifically designed to measure fluorescence of collagen. Cervical LIF in non-pregnant women (n = 12) and postpartum women (n = 14) was also detected. The demographic characteristics of women at various times were recorded. The Bishop score at 40 to 41 gestational weeks (n = 37) before the onset of labor was analyzed. RESULTS: Cervical LIF values progressively declined from the non-pregnant state to late gestation (R = -0.836) and reached their lowest levels during parturition and then increased at postpartum. LIF values and the Bishop score were significantly negatively correlated (R = -0.83). In patients with a Bishop score ≥6, the first stage of labor was shortened with a decrease in LIF values (R = 0.718). CONCLUSIONS: Cervical collagen levels as measured by LIF could be a useful method for evaluating cervical maturity.


Assuntos
Maturidade Cervical , Colo do Útero , Colágeno , Parto Obstétrico , Feminino , Fluorescência , Humanos , Gravidez
3.
Reprod Sci ; 25(1): 74-85, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28436303

RESUMO

OBJECTIVES: To estimate the effects and mechanisms of choline, an essential nutrient and a selective α7 nicotinic acetylcholine receptor (α7nAChR) agonist, on the prevention of symptoms and the effects on the cholinergic anti-inflammatory pathways (CAP) in a lipopolysaccharide (LPS)-induced inflammatory response in a rat model. METHODS: Inflammation was induced by LPS treatment (1.0 µg LPS/kg body weight) on gestational day (GD) 14. Nonpregnant and pregnant Sprague Dawley rats were placed on a normal choline diet (1.1 g/kg) or supplemented choline diet (5.0 g/kg) from GDs 1 to 20. Systolic blood pressure (SBP), urinary albumin, and pregnancy outcomes were recorded. On GD 20, serum and placentas were assayed for cytokines. Western blots were used to determine the expression of placenta α7nAChR and components of the α7nAChR-CAP, including nuclear factor-κB (NF-κB) and protein kinase B (AKT). Immunohistochemistry was used to localize placental sites for the p65 subunit of NF-κB. RESULTS: Lipopolysaccharide significantly increased SBP and urinary albumin and decreased pregnancy outcomes, and these effects were partially reversed by higher choline treatment. Choline supplementation also significantly attenuated the LPS-induced increase in serum and placental inflammatory cytokines, decreased the expression of placental α7nAChR, lowered the activation of NF-κB signaling in placenta mononuclear cells, and inhibited placental AKT phosphorylation. CONCLUSION: This study confirms that LPS induces inflammatory conditions in pregnant rats and shows that choline supplementation protects against the inflammatory symptoms through its action on α7nAChR and CAP. These observations have important implications for the prevention and treatment of inflammatory responses associated with pregnancy.


Assuntos
Colina/uso terapêutico , Suplementos Nutricionais , Inflamação/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Animais , Colina/administração & dosagem , Citocinas/metabolismo , Feminino , Inflamação/induzido quimicamente , Inflamação/metabolismo , Lipopolissacarídeos , Placenta/metabolismo , Gravidez , Substâncias Protetoras/administração & dosagem , Ratos , Ratos Sprague-Dawley
4.
Reprod Sci ; 24(8): 1214-1220, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28715964

RESUMO

OBJECTIVE: Patient-controlled epidural analgesia (PCEA), used to relieve pain during delivery, delays labor but the mechanism is unknown. The aim was to investigate the effects of PCEA on uterine and abdominal muscles electromyographic (EMG) activity during the second stage of labor. METHODS: This study included 45 nulliparous pregnant women without PCEA, 42 women with standard PCEA treatment given during the first stage of labor and stopped near the end of the first stage, and 22 women with standard PCEA treatment with continued use throughout the first and second stages of labor. The EMG signals were recorded from the abdominal surface using PowerLab hardware and LabChart software (ADInstruments, New South Wales, Australia) and filtered to separate uterine and abdominal EMG. Various EMG burst parameters were obtained. RESULTS: There are no differences ( P > .05) in the age, body mass index, fetal weight, and Apgar scores between the patients from the various groups. PCEA (both stopped and continued) inhibits ( P < .05) duration, number of bursts, and root mean square of uterine EMG. PCEA also produces statistically significant ( P < .001) reductions in abdominal EMG. The decrease in EMG activity is accompanied by a significant ( P < .001) prolongation of the second stage duration (PCEA continued = 95.08 ± 8.60 minutes, PCEA stopped = 79.39 ± 6.25 minutes, no PCEA = 61.00 ± 7.23 minutes). CONCLUSION: PCEA suppresses uterine and abdominal muscle EMG during the second stage of labor but inhibition depends upon the treatment schedule. PCEA prolongs the duration of labor by inhibition of uterine and abdominal muscle and neural activity.


Assuntos
Músculos Abdominais/fisiologia , Analgesia Epidural , Analgesia Controlada pelo Paciente , Segunda Fase do Trabalho de Parto/fisiologia , Miométrio/fisiologia , Músculos Abdominais/efeitos dos fármacos , Adulto , Anestésicos Locais/administração & dosagem , Eletromiografia , Feminino , Humanos , Segunda Fase do Trabalho de Parto/efeitos dos fármacos , Miométrio/efeitos dos fármacos , Gravidez
5.
J Mol Graph Model ; 72: 156-167, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28092834

RESUMO

The NO3-initiated reactions of CH3OCH3 and CH3OCH2CH3 have been investigated by the BHandHLYP method in conjunction with the 6-311G(d,p) basis set. Thermodynamic and kinetic data are further refined using the comparatively accurate CCSD(T) method. According to the values of reaction enthalpies (ΔHr,298θ) and reaction Gibbs free energies (ΔGr,298θ) from CH3OCH2CH3 with NO3 system, we find that H-abstraction pathway from the α-CH2 group is more exothermic. It is further confirmed by the calculated CH bond dissociation energy of CH3OCH2CH3 molecule. All the rate constants, computed through means of canonical variational transition state with small-curvature tunneling correction, are fitted to the three-parameter expressions k1=1.54×10-23T3.34exp(-1035.53/T) and k2=3.55×10-26T4.31exp(-281.24/T)cm3molecule-1s-1 and branching ratios are computed over the temperature range 200-600K. The branching ratios are also discussed. The atmospheric lifetimes of CH3OCH3 and CH3OCH2CH3 determined by the NO3 radical are about 270 and 29days, respectively.


Assuntos
Atmosfera/química , Éteres/química , Modelos Moleculares , Nitratos/química , Elétrons , Cinética , Conformação Molecular , Estereoisomerismo , Termodinâmica , Vibração
6.
Reprod Sci ; 24(3): 471-477, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27436367

RESUMO

OBJECTIVE: To record and characterize electromyography (EMG) from the uterus and abdominal muscles during the nonlabor to first and second stages of labor and to define relationships to contractions. METHODS: Nulliparous patients without any treatments were used (n = 12 nonlabor stage, 48 during first stage and 33 during second stage). Electromyography of both uterine and abdominal muscles was simultaneously recorded from electrodes placed on patients' abdominal surface using filters to separate uterine and abdominal EMG. Contractions of muscles were also recorded using tocodynamometry. Electromyography was characterized by analysis of various parameters. RESULTS: During the first stage of labor, when abdominal EMG is absent, uterine EMG bursts temporally correspond to contractions. In the second stage, uterine EMG bursts usually occur at same frequency as groups of abdominal bursts and precede abdominal bursts, whereas abdominal EMG bursts correspond to contractions and are accompanied by feelings of "urge to push." Uterine EMG increases progressively from nonlabor to second stage of labor. CONCLUSIONS: (1) Uterine EMG activity can be separated from abdominal EMG events by filtering. (2) Uterine EMG gradually evolves from the antepartum stage to the first and second stages of labor. (3) Uterine and abdominal EMG reflect electrical activity of the muscles during labor and are valuable to assess uterine and abdominal muscle events that control labor. (4) During the first stage of labor uterine, EMG is responsible for contractions, and during the second stage, both uterine and abdominal muscle participate in labor.


Assuntos
Músculos Abdominais/fisiologia , Trabalho de Parto/fisiologia , Miométrio/fisiologia , Contração Uterina/fisiologia , Adulto , Eletromiografia , Feminino , Humanos , Paridade , Gravidez
7.
Placenta ; 39: 77-83, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26992678

RESUMO

INTRODUCTION: Previous work conducted by our group has shown that nicotine reduces lipopolysaccharide (LPS)-induced systemic inflammatory responses and protects fetuses in pregnant Sprague-Dawley (SD) rats. In the present study, we aim to evaluate the influence of nicotine on rat placenta, including cytokine release, leukocyte infiltration, and α7 nicotinic acetylcholine receptor (α7-nAChR) expression. METHODS: Placental tissues of SD rats on gestation day 14 (GD14) were obtained and cultured in the presence or absence of LPS and/or nicotine. Culture media after 24 h were analyzed for cytokines release using Luminex. Other pregnant SD rats were first pretreated with nicotine on GD14 and GD15, followed by LPS injection on GD16. Placentas were collected on GD18 for H&E staining to evaluate leukocyte density and for real-time PCR and western blotting to identify the α7-nAChR expression in different groups. RESULTS: Nicotine suppresses LPS-stimulated placental proinflammatory cytokines (IL-1, IL-2, IL-6, TNF-α, IFN-γ) production except IL-17 in vitro, and reduces leucocytes infiltration in the placental chorionic plate caused by LPS in vivo. Moreover, LPS increases the α7-nAChR protein expression in placentas while pretreatment of nicotine inhibits it. DISCUSSION: These data show that nicotine suppresses LPS-induced placental inflammation by inhibition of cytokine release and infiltration of leukocytes into the placenta, and regulates the increased expression of α7-nAChR in placenta after LPS treatment. Nicotine and other nicotinic agonists may be an alternative therapeutic strategy for placental inflammation.


Assuntos
Quimiotaxia de Leucócito/efeitos dos fármacos , Citocinas/metabolismo , Lipopolissacarídeos/farmacologia , Nicotina/farmacologia , Placenta/efeitos dos fármacos , Animais , Quimiotaxia de Leucócito/fisiologia , Feminino , Leucócitos/efeitos dos fármacos , Leucócitos/fisiologia , Placenta/imunologia , Placenta/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley
8.
J Matern Fetal Neonatal Med ; 29(22): 3677-81, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26864001

RESUMO

OBJECTIVE: The objective of this study is to estimate changes in the surface area of the ectocervix (CA) in women during pregnancy and compare this to postpartum and non-pregnant states. METHODS: CA was evaluated in 210 normal nulliparous women divided into groups from early to late gestation, 40 postpartum women, and 25 non-pregnant women. CA in cm(2) was estimated from analysis of images taken with an endoscope of the cervical face and an mm scale. An mm scale was also used to determine fornix length and fornix area computed. RESULTS: The face, fornix, and total areas of the CA of non-pregnant and postpartum groups are significantly smaller (p < 0.001) than these areas in groups during pregnancy. Generally, the CA of the face, fornix, and total area are also less in early pregnancy compared with late gestation (p < 0.01 to <0.001). Total CA correlates with gestational age (r = 0.196, p < 0.004). CONCLUSIONS: (1) During pregnancy, CA slowly and progressively increases to >75% area compared with CA of non-pregnant patients and then reverts back to low CA postpartum. (2) Increases in CA during pregnancy occur in both the face and fornix areas. (3) Increases in CA reflect enlargement in cervical volume and remodeling during pregnancy.


Assuntos
Colo do Útero/fisiologia , Período Pós-Parto/fisiologia , Gravidez/fisiologia , Adulto , Colo do Útero/anatomia & histologia , Colo do Útero/diagnóstico por imagem , Endoscopia , Feminino , Idade Gestacional , Humanos
9.
Reprod Sci ; 22(11): 1350-7, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25824008

RESUMO

OBJECTIVE: To investigate the effect of patient-controlled epidural analgesia (PCEA) on uterine electromyography (EMG) activity in term pregnant women during labor. METHODS: Nulliparous pregnant women in spontaneous term labor (N = 30) were enrolled (PCEA group, n = 20 and control group, n = 10). Five time periods (30 minutes each) were defined for noninvasive abdominal recordings and analysis of uterine EMG activity, that is, period I: before PCEA treatment with 2-cm cervical dilation; periods II to IV: each period successively at 30, 60, and 120 minutes after PCEA; and period V: second stage of labor with cervix at 10 cm dilation. Control patients without PCEA were monitored during the same times. The number of bursts/30 min, power density spectrum peak frequency, mean amplitude, and duration of uterine EMG bursts were measured to assess uterine EMG activity. Maternal, fetal, and labor characteristics were also recorded. Data were analyzed by analysis of variance followed by other tests. RESULTS: Electromyography parameters are significantly lower (P < .001) after PCEA (periods II to IV) compared to controls but similar between groups by period V (P > .05). Also, patients with PCEA have a slower rate of cervical dilation (P < .003, period IV only) and longer labor in both stage 1 and stage 2 (P < .05). All patients have similar (P > .05) positive labor outcomes. CONCLUSIONS: Patient-controlled epidural analgesia initially suppresses uterine EMG and slows cervical dilation thereby prolonging labor. However, the EMG activity recovers with labor progress with no effects on delivery outcomes.


Assuntos
Analgesia Epidural , Analgesia Obstétrica , Analgesia Controlada pelo Paciente , Eletromiografia , Início do Trabalho de Parto , Dor do Parto/tratamento farmacológico , Paridade , Contração Uterina/efeitos dos fármacos , Administração Intravenosa , Adulto , Analgésicos Opioides/administração & dosagem , Anestésicos Locais/administração & dosagem , Bupivacaína/administração & dosagem , Bupivacaína/análogos & derivados , Estudos de Casos e Controles , China , Feminino , Humanos , Dor do Parto/diagnóstico , Dor do Parto/fisiopatologia , Primeira Fase do Trabalho de Parto , Levobupivacaína , Medição da Dor , Valor Preditivo dos Testes , Gravidez , Sufentanil/administração & dosagem , Nascimento a Termo , Fatores de Tempo , Resultado do Tratamento
10.
Am J Obstet Gynecol ; 212(6): 786.e1-9, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25640046

RESUMO

OBJECTIVE: The objective of the study was to determine the effects of electrical stimulation (ES) on cervical ripening in pregnant and nonpregnant rats. STUDY DESIGN: Timed pregnant and nonpregnant Sprague-Dawley rats (n = 6-7/group) were used. Cervical ES for pregnant rats was performed in vivo on day 15 of gestation by inserting an electrical probe into the vagina in contact with the cervix. Parameters of ES varied from 0.1 to 0.2 mA, 10 pulses per second, 20 milliseconds pulse duration, and repeating pulses for 15, 30, 60, and 120 minutes for pregnant ES groups and similar times for sham control groups with electrode but without ES. Nonpregnant ES groups were stimulated with only 0.2 mA for 30 minutes. Cervical collagen was measured in controls and following ES at various times using light-induced fluorescence (LIF) of collagen. Photographs were taken following ES, and some rats were killed, the cervices were isolated, and cervical extensibility was estimated. RESULTS: LIF values of pregnant rats are significantly lower (P < .001) and extensibility greater (P < .05) in the ES treatment groups compared with the control groups on days 16 and 17 of pregnancy. Similarly LIF is lower (P < .05) and extensibility values greater (P < .05) in nonpregnant rats treated with ES. No adverse effects, including altered delivery time, pup weights, or damage to cervix, were produced by low current levels of ES needed to soften the cervix. CONCLUSION: The following conclusions were reached: (1) application of ES rapidly produces softening and ripening of the cervix in pregnant and nonpregnant rats; (2) ES treatment does not produce early delivery; (3) the exact mechanism for ES ripening is not yet known; and (4) ES might be used clinically to ripen the cervix when needed.


Assuntos
Maturidade Cervical/fisiologia , Estimulação Elétrica , Animais , Estimulação Elétrica/métodos , Feminino , Parto , Gravidez , Ratos , Ratos Sprague-Dawley
11.
J R Soc Interface ; 11(101): 20140726, 2014 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-25401181

RESUMO

The smooth muscle cells of the uterus contract in unison during delivery. These cells achieve coordinated activity via electrical connections called gap junctions which consist of aggregated connexin proteins such as connexin43 and connexin45. The density of gap junctions governs the excitability of the myometrium (among other factors). An increase in gap junction density occurs immediately prior to parturition. We extend a mathematical model of the myometrium by incorporating the voltage-dependence of gap junctions that has been demonstrated in the experimental literature. Two functional subtypes exist, corresponding to systems with predominantly connexin43 and predominantly connexin45, respectively. Our simulation results indicate that the gap junction protein connexin45 acts as a negative modulator of uterine excitability, and hence, activity. A network with a higher proportion of connexin45 relative to connexin43 is unable to excite every cell. Connexin45 has much more rapid gating kinetics than connexin43 which we show limits the maximum duration of a local burst of activity. We propose that this effect regulates the degree of synchronous excitation attained during a contraction. Our results support the hypothesis that as labour approaches, connexin45 is downregulated to allow action potentials to spread more readily through the myometrium.


Assuntos
Conexina 43/metabolismo , Conexinas/metabolismo , Modelos Biológicos , Contração Muscular/fisiologia , Miométrio/metabolismo , Transdução de Sinais/fisiologia , Feminino , Junções Comunicantes/metabolismo , Humanos
12.
Ultrasound Med Biol ; 40(9): 2107-12, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24972500

RESUMO

Application of focused ultrasound stimulation (FUS) to the rat cervix during pregnancy has significant physiologic effects. One-millisecond-long pulses of 680-kHz ultrasound with a repetition frequency of 25 Hz, at ISPTA (spatial-peak, temporal-average intensity) of 1, 2 and 4W/cm(2), were applied to the rat abdomen over the cervix. FUS produced a significant change in cervical elasticity known as softening, which is part of the ripening process, comparable to the degree seen just before delivery. Timed-pregnant Sprague-Dawley rats (n = 40) were used. During gestation, the FUS system was applied to the cervix for variable times up to 1 h. Daily measurements of cervix light-induced florescence were made to estimate changes in softening. In addition, cervical stretch estimates of softening were made of isolated cervices of control and FUS-treated rats to measure distensiblity. The ultrasound power with ISPPA (spatial-peak, pulse-average intensity) of 40 W/cm(2) was considered tolerable; the U.S. Food and Drug Administration regulatory limit is 190 W/cm(2) for both the body periphery and the fetus. This is the first report of alterations induced by ultrasound in the connective tissue of the cervix and suggests the therapeutic application of ultrasound for the facilitation of labor and delivery.


Assuntos
Colo do Útero/diagnóstico por imagem , Terapia por Ultrassom/métodos , Animais , Elasticidade , Feminino , Modelos Animais , Gravidez , Ratos Sprague-Dawley , Ultrassonografia
13.
Am J Obstet Gynecol ; 211(5): 538.e1-7, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24769008

RESUMO

OBJECTIVE: The objective of the study was to examine the effects of nicotine, an α7 nicotinic acetylcholine receptor agonist, on lipopolysaccharide (LPS)-induced inflammatory responses in rats during pregnancy. STUDY DESIGN: Pregnant Sprague Dawley rats were randomly divided into groups (n = 6 rats/group): group 1 rats each received a single intraperitoneal injection of LPS (25 µg/kg) on gestation day 16; group 2 rats were first pretreated with nicotine (1 mg/kg per day, subcutaneously) on gestation days 14 and 15 and then were treated with single injections of LPS on gestational day 16; group 3 rats were treated with the vehicle (saline) used for groups 2 and 3 (controls). Maternal blood was collected at 6 hours and 24 hours after LPS and vehicle treatments and assayed for tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), and interleukin-10 (IL-10). In addition, the number of live pups and pup weights were obtained at the time of delivery. RESULTS: LPS treatment significantly (P < .001) elevates maternal blood levels of TNF-α and IL-6 but not IL-10 (P > .05). Nicotine treatment significantly reduces LPS-induced TNF-α and IL-6 concentrations (P < .001) but does not change (P > .05) IL-10 levels. The number of live pups in the LPS group are significantly lower (P < .001) than the vehicle treated controls, and nicotine treatment significantly (P < .011) reverses this change. Similarly, fetal weights are lower following LPS (P < .016) and higher (P < .024) in the group treated with nicotine plus LPS. CONCLUSION: Nicotine reduces the LPS-induced inflammatory responses and rescues the fetus in rats during pregnancy. Thus, nicotine exerts dramatic antiinflammatory effects. These observations have important implications for control of inflammatory responses during pregnancy.


Assuntos
Peso ao Nascer/efeitos dos fármacos , Feto/efeitos dos fármacos , Inflamação/imunologia , Interleucina-10/imunologia , Interleucina-6/imunologia , Lipopolissacarídeos/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Resultado da Gravidez , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Animais , Feminino , Injeções Intraperitoneais , Gravidez , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/imunologia , Receptor Nicotínico de Acetilcolina alfa7/agonistas
14.
Am J Obstet Gynecol ; 210(1): 76.e1-7, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24036401

RESUMO

OBJECTIVE: The aims of this study were to examine the effects of nicotine treatment on the length of gestation, on fetal outcome, on cervical ripening, and on uterine contractility during pregnancy in rats. STUDY DESIGN: Pregnant rats were treated with various concentrations of nicotine (0.25, 0.5, 1, 2 mg/kg/d, subcutaneously). Delivery times and fetal weights were obtained. Cervical collagen cross-links were assessed in vivo by collagen light-induced fluorescence (LIF), and cervical resistance to stretch was measured by in vitro extensibility tests. RESULTS: Delivery time is significantly (P = .002) prolonged after high-dose nicotine treatments. There are no significant changes in pup weights and placenta weights after nicotine treatments. Cervical collagen LIF and extensibility progressively decrease throughout pregnancy in control rats. Nicotine-treated rats showed significant (P < .001) cervical resistance to stretch and higher LIF compared with the control rats. Nicotine treatment in vitro had little effect on uterine contractility. CONCLUSION: Nicotine exposure during pregnancy prolongs gestation and inhibits cervical ripening, possibly by suppression of a cholinergic antiinflammatory response.


Assuntos
Maturidade Cervical/efeitos dos fármacos , Colo do Útero/efeitos dos fármacos , Colágeno/metabolismo , Nicotina/farmacologia , Contração Uterina/efeitos dos fármacos , Animais , Colo do Útero/fisiologia , Feminino , Gravidez , Resultado da Gravidez , Ratos , Ratos Sprague-Dawley , Contração Uterina/fisiologia
15.
Steroids ; 78(9): 909-19, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23607964

RESUMO

Progesterone receptor (PR) plays a key role in reproductive functions, and compounds that inhibit progesterone action (antiprogestins) have potential use in the treatment of estrogen- and progesterone-dependent diseases, including uterine leiomyomas and breast cancer. In the present study, we chemically synthesized novel 17-fluorinated steroids and evaluated the cytotoxicity profiles of these compounds in T47D breast cancer cells compared to the activity of known antiprogestins, including ZK230 211, RU-486, CDB2914, CDB4124 and ORG33628. We analyzed in vitro receptor-binding assays and PR-transactivation assays to establish the antiprogestational activity of these molecules. The representative antiprogestin EC304 was found to inhibit in vitro tumorigenicity in a dose-dependent fashion in T47D cells by a colony formation assay at 1 and 10nM concentrations. The potent in vivo antiprogestational activity of EC304 was also demonstrated in an antinidation assay for the interruption of early pregnancy in rats. The strong antiprogestational activity and absence of antiglucocorticoid activity in EC compounds may demonstrate their utility in the treatment of leiomyoma, endometriosis and breast cancer.


Assuntos
Antineoplásicos/síntese química , Estrenos/síntese química , Hidrocarbonetos Fluorados/síntese química , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Implantação do Embrião/efeitos dos fármacos , Estrenos/farmacologia , Feminino , Halogenação , Humanos , Hidrocarbonetos Fluorados/farmacologia , Masculino , Fosforilação , Gravidez , Processamento de Proteína Pós-Traducional , Ratos , Ratos Sprague-Dawley , Receptores de Progesterona/antagonistas & inibidores , Receptores de Progesterona/metabolismo
16.
Steroids ; 78(2): 255-67, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23178161

RESUMO

A series of antiprogestins have been synthesized by partially fluorinating the steroid molecule in positions relevant for receptor binding. By introducing fluorine at the exo-methylene of the 17 spirofuran ring, we obtained partial agonists (mesoprogestins) with significant applications for antiproliferative and antiovulatory treatment strategies in gynecological therapy such as uterine fibroids, endometriosis and heavy menstrual bleeding. Compared to the standard drug RU486, our synthesized compounds exhibited considerable dissociation between antiprogestational and antiglucocorticoid PR receptors. Furthermore, our studies have shown that pure antiprogestins can be generated by partially fluorinating the 17 propenyl and propynl group or by substituting the 4' acetyl phenyl group in the 11 position using trifluromethyl group.


Assuntos
Halogenação/efeitos dos fármacos , Antagonistas de Hormônios/síntese química , Antagonistas de Hormônios/farmacologia , Progestinas/síntese química , Progestinas/farmacologia , Animais , Feminino , Cobaias , Células HEK293 , Humanos , Espectroscopia de Ressonância Magnética , Mifepristona/análogos & derivados , Mifepristona/química , Mifepristona/farmacologia , Progestinas/antagonistas & inibidores , Receptores de Estrogênio/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Progesterona/antagonistas & inibidores , Receptores de Progesterona/metabolismo , Vagina/citologia , Vagina/efeitos dos fármacos
17.
Asian Pac J Cancer Prev ; 13(9): 4689-93, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23167403

RESUMO

Lung cancer is the most common type of cancer and one of the leading causes of death in the world. Genetic factors play an important role in its development. PDCD6, the encoding gene for programmed cell death protein 6, may function as a tumor suppressor gene. Non-small cell lung cancer (NSCLC) contributes about 80% to newly histologically diagnosed lung cancer patients. To explore the relationship between PDCD6 and NSCLC, we examined two single nucleotide polymorphisms(rs3756712 G/T andrs4957014 G/T, both in the intron region) of the PDCD6gene.A hospital-based case-control study was carried out including 302 unrelated NSCLC patients and 306 healthy unrelated subjects. Significantly increased NSCLC risk was found to be associated with the T allele of rs4957014 (P=0.027, OR=0.760, 95%CI=0.596-0.970). The genotype and allele frequencies of rs3756712 did not shown any significant difference between NSCLC group and controls (P=0.327, OR=0.879, 95%CI=0.679- 1.137). In conclusion, we firstly demonstrated the association between the PDCD6 gene and risk of NSCLC in a Chinese Han population.


Assuntos
Adenocarcinoma/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas de Ligação ao Cálcio/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Idoso , Povo Asiático/genética , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , China , Intervalos de Confiança , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Razão de Chances
18.
Am J Obstet Gynecol ; 206(3): 254.e1-5, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22244470

RESUMO

OBJECTIVE: Various tocolytics are used to suppress uterine contractility in patients in preterm labor. Progesterone (P4) is used in patients at high risk for preterm delivery. In this study, we evaluated the effects of various tocolytics with and without P4 to examine effects on uterine contractility. STUDY DESIGN: Uterine tissues (n = 280) from women undergoing cesarean at term were exposed in vitro to various agents (vehicle, magnesium sulfate [MgSO(4)], nifedipine, indomethacin, or pinacidil-all with and without P4). Contractility was measured before and after addition of the various agents. RESULTS: P4 alone at 10(-5) mol/L concentration has little effect to inhibit contractility (P ≥ .05). MgSO(4) (2-8 × 10(-3) mol/L) inhibits uterine contractility (P < .05) but there is no change when combined with P4 (P > .05). Nifedipine (10(-8) mol/L) and indomethacin (10(-5) mol/L) inhibit contractions alone (P < .05) and to a greater extent when combined with P4 (P < .05). P4 significantly (P < .05) reduced the effects of pinacidil (10(-6.5) mol/L). CONCLUSION: Combinations of P4 with nifedipine or indomethacin, but not MgSO(4), might be used to effectively suppress preterm labor.


Assuntos
Miométrio/efeitos dos fármacos , Trabalho de Parto Prematuro/prevenção & controle , Progesterona/farmacologia , Tocolíticos/farmacologia , Contração Uterina/efeitos dos fármacos , Adulto , Feminino , Humanos , Indometacina/farmacologia , Sulfato de Magnésio/farmacologia , Nifedipino/farmacologia , Pinacidil/farmacologia , Gravidez
19.
Acta Obstet Gynecol Scand ; 90(10): 1057-69, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21564026

RESUMO

Progestin supplementation appears to be a promising approach to both preventing initiation of preterm labor and treating it once it is already established, given the role of progesterone in maintaining pregnancy, as well as support from basic and clinical research. Progesterone and 17α-hydroxyprogesterone acetate slow the process of cervical ripening, and this is the rationale for prophylactic long-term progestin supplementation mostly studied so far. However, progesterone (but not 17α-hydroxyprogesterone acetate) also inhibits myometrial activity even after the cervix has already ripened. Moreover, these effects depend greatly on the vehicle used and the route of administration. Understanding different mechanisms of action, as well as the importance of progestin formulation, vehicle and route of administration, is the key to finding the optimal progestin treatment for prevention of preterm birth.


Assuntos
Resultado da Gravidez , Nascimento Prematuro/prevenção & controle , Progestinas/administração & dosagem , Administração Intravaginal , Maturidade Cervical/efeitos dos fármacos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Recém-Nascido , Injeções Intramusculares , Trabalho de Parto Prematuro/tratamento farmacológico , Trabalho de Parto Prematuro/prevenção & controle , Gravidez , Nascimento Prematuro/tratamento farmacológico , Prevenção Primária/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto
20.
Am J Obstet Gynecol ; 205(1): 82.e15-20, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21497789

RESUMO

OBJECTIVE: The purpose of this study was to determine whether optical methods can estimate cervix function during pregnancy and whether progestins modify this process. STUDY DESIGN: Photos of the external cervix of timed-pregnant rats were taken every other day from day 13 until postpartum day 5 after daily treatments with vehicle (controls) or progestin treatments (progesterone, subcutaneously or vaginally; 17-alpha-hydroxyprogesterone caproate [17P] and RU-486 subcutaneously, once on day 16). The surface area of the cervix was estimated from photos. RESULTS: The surface area of cervix increases throughout pregnancy and reverses after delivery in controls. In the progesterone subcutaneously or 17P subcutaneously groups, increases in surface area are lower (17P group until day 19 only; P < .05). Vaginal progesterone does not prevent surface area increases. Only the progesterone subcutaneously blocked delivery. RU-486 increases the surface area of the cervix (P < .05) during preterm delivery. CONCLUSION: An optical method is useful for quantitative assessment of the cervix and evaluation of agents that modify cervical function.


Assuntos
Colo do Útero/efeitos dos fármacos , Trabalho de Parto/efeitos dos fármacos , Trabalho de Parto Prematuro/induzido quimicamente , Fotografação/métodos , Progestinas/farmacologia , 17-alfa-Hidroxiprogesterona , Animais , Feminino , Mifepristona/farmacologia , Gravidez , Resultado da Gravidez , Progesterona/farmacologia , Ratos , Ratos Sprague-Dawley
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