RESUMO
Cisplatin is one of the most potent anti-cancer drugs used for the treatment of various solid tumors, yet it has several side effects that may limit its clinical use. Hepatotoxicity is one of the most serious side effects as it may lead to liver failure. Several mechanisms including oxidative stress, inflammation, and apoptosis have been examined in cisplatin-induced hepatotoxicity. Protocatechuic acid (Proto) which is naturally occurring phenolic acid has shown different biological activity as antioxidant, anti-inflammatory, and anti-apoptotic. In this study, we investigate the protective effect of Proto at two doses 100 and 150 mg/kg on hepatotoxicity induced by a single injection of 10 mg/kg cisplatin in female albino mice. The present study demonstrates for the first time that Proto administration (100 and 150 mg/Kg) significantly attenuates cisplatin-induced changes in liver function [increase serum albumin and decrease liver injury markers ALT, AST, GGT, and bilirubin]. This was associated with marked hepatic antioxidant effects [decrease MDA and NO levels, increase GSH and SOD activity]. Moreover, Proto reduced cisplatin-induced apoptosis in the liver through decreasing caspase-3, annexin-V, and BAX. Both doses suppressed cisplatin-induced expression of iNOS and NF-á´B p65 subunit and pro-inflammatory cytokines (IL-6 and TNF-α). Also, Proto improved histopathological examination of the liver. The present findings reveal that the antioxidant, anti-inflammatory, and anti-apoptotic effects of Proto are the main mechanisms by which Proto can ameliorate cisplatin-induced liver injury.
Assuntos
Cisplatino/efeitos adversos , Hidroxibenzoatos/farmacologia , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cisplatino/farmacologia , Cisplatino/toxicidade , Citocinas/metabolismo , Feminino , Hidroxibenzoatos/metabolismo , Fígado/metabolismo , Camundongos , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacosRESUMO
Hepatic damage is one of the most common complications related to cisplatin (Cis) use. Recently, liver protection lines are being discovered to avoid hepatic cell death as a result of oxidative, inflammatory, and apoptotic disturbance. Limited data reported the hepatoprotective effect of vinpocetine (Vin) in acute liver injury models. This study was designed to determine the potential protective effect of Vin (10-30 mg/kg, orally) against Cis-induced liver injury (10 mg/kg, IP) in mice. Vin administration for 1 week before Cis injection until the end of the experiment. On the 6th day after Cis injection, mice were anesthetized, blood and tissue samples were collected. Hepatic function, histological changes, oxidative stress, inflammation, and apoptotic markers were investigated. Vin administration ameliorated liver injury as indicated by decreased liver injury parameters; serum aminotransferases, ALK-P, GGT, and bilirubin, restored the anti-oxidant status by decrease MDA and NOx , and increased GSH and SOD, inhibited inflammation (IL-6, TNF-α, NFκB-p65, and iNOS) and apoptosis (Annexin-V, Bax, and Caspase-3) parameters. Vin confers dose-dependent protection against Cis-induced liver injury. The hepatoprotective effect of Vin involved anti-oxidative, anti-inflammatory, and anti-apoptotic activities.
Assuntos
Anexina A5/metabolismo , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Cisplatino/toxicidade , Fígado/efeitos dos fármacos , Alcaloides de Vinca/farmacologia , Proteína X Associada a bcl-2/metabolismo , Animais , Biomarcadores/sangue , Peso Corporal/efeitos dos fármacos , Feminino , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Tamanho do Órgão/efeitos dos fármacosRESUMO
Perinatal depression is associated with serious risks for the mother, baby, and family. When considering treating perinatal depression with a drug indicated for the treatment of depression, the major concerns are whether the drug increases the risks of teratogenicity, pregnancy complications, poor neonatal adaptation, or neurodevelopmental disorders. Although different studies have produced different results, the majority have not shown increases in risk for selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, or the noradrenergic/dopaminergic drug bupropion. In this review we will discuss the reproductive safety data for these medications as well as monoamine oxidase inhibitors and benzodiazepines.
Assuntos
Depressão/tratamento farmacológico , Complicações na Gravidez/tratamento farmacológico , Anormalidades Induzidas por Medicamentos , Aborto Espontâneo , Antidepressivos Tricíclicos/uso terapêutico , Transtorno do Espectro Autista , Benzodiazepinas/uso terapêutico , Bupropiona/uso terapêutico , Desenvolvimento Infantil , Feminino , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Inibidores da Monoaminoxidase/uso terapêutico , Síndrome da Persistência do Padrão de Circulação Fetal , Hemorragia Pós-Parto , Gravidez , Complicações na Gravidez/psicologia , Nascimento Prematuro , Efeitos Tardios da Exposição Pré-Natal , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêuticoRESUMO
Irreversible inactivation of alpha-thrombin (T) by the serpin, heparin cofactor II (HCII), is accelerated by ternary complex formation with the glycosaminoglycans (GAGs) heparin and dermatan sulfate (DS). Low expression of human HCII in Escherichia coli was optimized by silent mutation of 27 rare codons and five secondary Shine-Dalgarno sequences in the cDNA. The inhibitory activities of recombinant HCII, and native and deglycosylated plasma HCII, and their affinities for heparin and DS were compared. Recombinant and deglycosylated HCII bound heparin with dissociation constants (K(D)) of 6+/-1 and 7+/-1 microM, respectively, approximately 6-fold tighter than plasma HCII, with K(D) 40+/-4 microM. Binding of recombinant and deglycosylated HCII to DS, both with K(D) 4+/-1 microM, was approximately 4-fold tighter than for plasma HCII, with K(D) 15+/-4 microM. Recombinant HCII, lacking N-glycosylation and tyrosine sulfation, inactivated alpha-thrombin with a 1:1 stoichiometry, similar to plasma HCII. Second-order rate constants for thrombin inactivation by recombinant and deglycosylated HCII were comparable, at optimal GAG concentrations that were lower than those for plasma HCII, consistent with its weaker GAG binding. This weaker binding may be attributed to interference of the Asn(169)N-glycan with the HCII heparin-binding site.
Assuntos
Escherichia coli/metabolismo , Glicosaminoglicanos/metabolismo , Cofator II da Heparina/metabolismo , Sequência de Aminoácidos , Dermatan Sulfato/metabolismo , Ativação Enzimática , Fluorescência , Glicosilação , Cofator II da Heparina/química , Cofator II da Heparina/isolamento & purificação , Humanos , Cinética , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Peptídeos/química , Ligação Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Trombina/metabolismoRESUMO
Inactivation of thrombin (T) by the serpins heparin cofactor II (HCII) and antithrombin (AT) is accelerated by a heparin template between the serpin and thrombin exosite II. Unlike AT, HCII also uses an allosteric interaction of its NH(2)-terminal segment with exosite I. Sucrose octasulfate (SOS) accelerated thrombin inactivation by HCII but not AT by 2000-fold. SOS bound to two sites on thrombin, with dissociation constants (K(D)) of 10 +/- 4 microm and 400 +/- 300 microm that were not kinetically resolvable, as evidenced by single hyperbolic SOS concentration dependences of the inactivation rate (k(obs)). SOS bound HCII with K(D) 1.45 +/- 0.30 mm, and this binding was tightened in the T.SOS.HCII complex, characterized by K(complex) of approximately 0.20 microm. Inactivation data were incompatible with a model solely depending on HCII.SOS but fit an equilibrium linkage model employing T.SOS binding in the pathway to higher order complex formation. Hirudin-(54-65)(SO(3)(-)) caused a hyperbolic decrease of the inactivation rates, suggesting partial competitive binding of hirudin-(54-65)(SO(3)(-)) and HCII to exosite I. Meizothrombin(des-fragment 1), binding SOS with K(D) = 1600 +/- 300 microm, and thrombin were inactivated at comparable rates, and an exosite II aptamer had no effect on the inactivation, suggesting limited exosite II involvement. SOS accelerated inactivation of meizothrombin 1000-fold, reflecting the contribution of direct exosite I interaction with HCII. Thrombin generation in plasma was suppressed by SOS, both in HCII-dependent and -independent processes. The ex vivo HCII-dependent process may utilize the proposed model and suggests a potential for oversulfated disaccharides in controlling HCII-regulated thrombin generation.
Assuntos
Anticoagulantes/metabolismo , Coagulação Sanguínea/fisiologia , Cofator II da Heparina/metabolismo , Sacarose/análogos & derivados , Trombina/metabolismo , Regulação Alostérica , Anticoagulantes/química , Anticoagulantes/farmacologia , Ligação Competitiva/efeitos dos fármacos , Ligação Competitiva/fisiologia , Coagulação Sanguínea/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Precursores Enzimáticos/metabolismo , Precursores Enzimáticos/farmacologia , Cofator II da Heparina/química , Hirudinas/metabolismo , Hirudinas/farmacologia , Humanos , Cinética , Modelos Químicos , Plasma , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacologia , Protrombina/metabolismo , Espectrometria de Fluorescência , Sacarose/química , Sacarose/metabolismo , Sacarose/farmacologia , Trombina/química , Trombina/farmacologiaRESUMO
OBJECTIVE: To promote prompt identification and treatment ofperinatal depression and enhance preventive care for women at risk. METHODS: Using MEDLINE and PubMed searches, we reviewed the recent research on the origins, course, and consequences of pregnancy-related depression. RESULTS: Depressive disorders are more common in pregnancy and postpartum than widely assumed, and there is no predictable protective effect of pregnancy. Relapse rates are high, and the postpartum period represents a time of increased vulnerability to depression. CONCLUSION: Early identification and treatment ofperinatal depression will minimize morbidity and mortality for the woman, the child, and the family.
Assuntos
Depressão Pós-Parto , Transtorno Depressivo , Complicações na Gravidez , Desenvolvimento Infantil , Pré-Escolar , Efeitos Psicossociais da Doença , Depressão Pós-Parto/diagnóstico , Depressão Pós-Parto/epidemiologia , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/epidemiologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Humanos , Lactente , Recém-Nascido , Programas de Rastreamento , Relações Mãe-Filho , Apego ao Objeto , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/epidemiologia , RiscoRESUMO
UNLABELLED: We sought to determine how frequently intraoperative transesophageal echocardiography (TEE) altered the planned surgical procedure and to assess the potential cost implications associated with these changes. A retrospective chart review was conducted at one university hospital. Cardiac surgical operative notes from July 1999 through June 2000 were reviewed. We interrogated all adult cardiac surgical records for patients scheduled for repair of coronary artery disease or valvular disease requiring the use of cardiopulmonary bypass. Cancellations based on TEE findings were included in the analysis. Of the 430 patient records reviewed, 24 procedures were ether canceled or changed on the basis of the intraoperative TEE examination (5.6%; 95% confidence interval, 3.6%-8.2%). Six of these cases involved valvular heart disease, and the remaining 18 involved the intraoperative diagnosis and repair of a patent foramen ovale. A cost-benefit analysis based on the 6 valvular diagnoses revealed a saving of $230 per patient. Assuming that unnecessary present or future operations may be avoided by altering the surgical plan on the basis of TEE findings, these preliminary data suggest that routine intraoperative TEE in cardiac surgery is beneficial and cost-effective. IMPLICATIONS: A review of 430 adult cardiac surgical records indicates that routine transesophageal echocardiography during cardiac surgery, including coronary artery surgery, is beneficial and cost-effective.