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1.
Eur Rev Med Pharmacol Sci ; 28(6): 2340-2350, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38567597

RESUMO

OBJECTIVE: The relationship between inflammatory markers and survival in many cancers has been investigated previously. Inflammatory markers may also offer the possibility of predicting surveillance in patients with malignant mesothelioma. Our study seeks to enhance comprehension of how variables such as the nutritional status and inflammation indices of malignant mesothelioma patients impact the disease's progression and prognosis. PATIENTS AND METHODS: This study included patients who were treated at the Erciyes University Medical Oncology Clinic between 2010 and 2022 and diagnosed with malignant mesothelioma. This is a retrospective single-center cohort study. Receiver Operating Characteristic (ROC) analysis was applied to determine the inflammation markers' optimal cut-off values with high sensitivity and specificity. Patients were categorized based on these values. The differences in overall survival (OS) and progression-free survival (PFS) between categorized groups were assessed using Log-rank curves and Kaplan-Meier tests. Multivariate analysis was performed using Cox regression analysis on statistically significant data. The relationship between inflammation markers and malignant mesothelioma survival was evaluated. RESULTS: There are 115 patients in this study. Pre-treatment high neutrophil to lymphocyte ratio (NLR) (HR: 1.34, 95% CI: 1.12-2.83, p=0.04), high pan-immune inflammation value (PIIV) (HR: 2.01, 95% CI: 1.32-4.79, p=0.03), and high systemic inflammation response index (SIRI) (HR: 1.34, 95% CI: 1.2-2.78, p=0.04) were associated with poor OS. Conversely, high advanced lung cancer inflammation index (ALI) (HR: 0.73, 95% CI: 0.53-0.84, p=0.03) and high hemoglobin-albumin-lymphocyte and platelet (HALP) (HR: 0.67, 95% CI: 0.23-0.78, p=0.02) were associated with favorable survival. CONCLUSIONS: Our study investigated the prognostic value of various inflammation markers in malignant mesothelioma patients and suggests that composite formulas like NLR, PIIV, SIRI, ALI, and HALP that incorporate CBC cells and nutritional parameters like albumin, height, and weight could more consistently and accurately predict malignant mesothelioma prognosis.


Assuntos
Mesotelioma Maligno , Humanos , Prognóstico , Mesotelioma Maligno/patologia , Estudos Retrospectivos , Estudos de Coortes , Linfócitos/patologia , Albuminas , Inflamação/patologia , Neutrófilos/patologia
2.
Pulmonology ; 2022 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-35115279

RESUMO

BACKGROUND: Substance use disorder (SUD) causes conditions such as cognitive and behavioral disorders, anxiety, depression, and social isolation it also causes acute airway inflammation by affecting airway bronchial dynamics. The current study aimed to investigate the lung function, respiratory muscle strength, and exercise capacity in patients with SUD. METHODS: One hundred-eighty three patients with SUD, a total of 119 healthy controls, 54 of whom were cigarette smokers and 65 of whom were non-smokers were included in the study. Spirometric tests, respiratory muscle strength (MIP and MEP), and the 6-Minute Walk Test (6-MWT) were assessed. The III National Health and Nutrition Examination Survey were used to evaluate respiratory symptoms in patients with SUD and cigarette smokers. RESULTS: 86.3% of the SUD patients included in the study were using heroin, 9.2% were cannabis, and 5.5% were spice. The most common symptom in both SUD patients and cigarette smokers was shortness of breath, wheezing, and sputum production. After post-hoc tests, the FVC (p = 0.002), FVC (%predicted) (p < 0.0001), FEV1 (p = 0.002), FEV1 (%predicted) (p < 0.0001), FEV1/FVC (%) (p < 0.0001), PEF (p < 0.0001) and FEF%25-75 (p < 0.0001) lung function parameters were significantly lower in SUD patients than non-smokers. In addition, it was found that MIP (p < 0.0001), MIP (%predicted) (p < 0.0001), MEP (p < 0.0001), and MEP (%predicted) (p < 0.0001) values of SUD patients were significantly lower than non-smokers. CONCLUSION: The study findings indicate that substance use has an effect on lung functions and the most commonly reported symptoms are shortness of breath, wheezing, and sputum production. In addition, respiratory muscle strength and exercise capacity were decreased in SUD patients compared to non-smokers.

3.
Bratisl Lek Listy ; 121(10): 749-752, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32955908

RESUMO

BACKGROUND: This study aims to investigate the effects of zinc and melatonin supplementation on lipid peroxidation in the brain cortex in DMBA-induced breast cancer in female rats. METHODS: A total of 42 recently weaned Wistar rats were divided into 5 groups as follows: Control (Group 1), DMBA Control (Group 2), DMBA+Zinc (Group 3), DMBA+Melatonin (Group 4), DMBA+Melatonin et Zinc (Group 5). At the end of the study, all animals were sacrificed by decapitation and Malondialdehyde (MDA) and glutathione (GSH) levels in brain cortex tissue samples were determined via spectrophotometric methods. RESULTS: The highest MDA levels were in the DMBA-treated group (Group 2) (p<0.05). MDA levels in Group 3, Group 4, and Group 5 were significantly lower than in group 2 (p<0.05). Also, GSH levels in group 3, 4, and 5 were significantly higher than in group 2 (p<0.05). CONCLUSION: There are no reports on whether DMBA-induced experimental breast cancer affects oxidative stress in brain tissue. In this respect, our study revealed that the increased brain cortex tissue damage in DMBA-induced breast cancer is alleviated by Zinc, melatonin, or combined zinc and melatonin treatment (Fig. 3, Ref. 26).


Assuntos
Neoplasias da Mama , Córtex Cerebral , Melatonina , Estresse Oxidativo , Zinco , Animais , Antracenos , Antioxidantes , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Suplementos Nutricionais , Feminino , Glutationa/metabolismo , Peroxidação de Lipídeos , Malondialdeído , Melatonina/farmacologia , Piperidinas , Ratos , Ratos Wistar , Zinco/farmacologia
4.
Arch Toxicol ; 92(11): 3415-3433, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30206662

RESUMO

Pentabromodiphenyl ethers (PBDE) are found in human tissue, in household dust, and in the environment, and a particular concern is the potential for the induction of cancer pathways from these fat-soluble persistent organic pollutants. Only one PBDE cancer study has been conducted and that was for a PBDE mixture (DE-71). Because it is not feasible to test all PBDE congeners in the environment for cancer potential, it is important to develop a set of biological endpoints that can be used in short-term toxicity studies to predict disease outcome after long-term exposures. In this study, PBDE-47 was selected as the test PBDE congener to evaluate and compare toxicity to that of the carcinogenic PBDE mixture. The toxicities of PBDE-47 and the PBDE mixture were evaluated at PND 22 in Wistar Han rat (Crl: WI (Han)) pups after in utero/postnatal exposure (0, 0.1, 15, or 50 mg/kg; dams, GD6-21; pups, PND 12-PND 21; oral gavage daily dosing). By PND 22, PBDE-47 caused centrilobular hypertrophy and fatty change in liver, and reduced serum thyroxin (T4) levels; similar effects were also observed after PBDE mixture exposure. Transcriptomic changes in the liver included induction of cytochrome p450 transcripts and up-regulation of Nrf2 antioxidant pathway transcripts and ABC membrane transport transcripts. Decreases in other transport transcripts (ABCG5 & 8) provided a plausible mechanism for lipid accumulation, characterized by a treatment-related liver fatty change after PBDE-47 and PBDE mixture exposure. The benchmark dose calculation based on liver transcriptomic data was generally lower for PBDE-47 than for the PBDE mixture. The up-regulation of the Nrf2 antioxidant pathway and changes in metabolic transcripts after PBDE-47 and PBDE mixture exposure suggest that PBDE-47, like the PBDE mixture (NTP 2016, TR 589), could be a liver toxin/carcinogen after long-term exposure.


Assuntos
Feto/efeitos dos fármacos , Éteres Difenil Halogenados/toxicidade , Fígado/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Animais , Colesterol/sangue , Feminino , Fígado/patologia , Masculino , Gravidez , Ratos , Ratos Wistar , Hormônios Tireóideos/sangue
5.
Toxicol Rep ; 5: 615-624, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29868454

RESUMO

Pentabrominated diphenyl ether (PBDE) flame retardants have been phased out in Europe and in the United States, but these lipid soluble chemicals persist in the environment and are found human and animal tissues. PBDEs have limited genotoxic activity. However, in a 2-year cancer study of a PBDE mixture (DE-71) (0, 3, 15, or 50 mg/kg (rats); 0, 3, 30, or 100 mg/kg (mice)) there were treatment-related liver tumors in male and female Wistar Han rats [Crl:WI(Han) after in utero/postnatal/adult exposure, and in male and female B6C3F1 mice, after adult exposure. In addition, there was evidence for a treatment-related carcinogenic effect in the thyroid and pituitary gland tumor in male rats, and in the uterus (stromal polyps/stromal sarcomas) in female rats. The treatment-related liver tumors in female rats were unrelated to the AhR genotype status, and occurred in animals with wild, mutant, or heterozygous Ah receptor. The liver tumors in rats and mice had treatment-related Hras and Ctnnb mutations, respectively. The PBDE carcinogenic activity could be related to oxidative damage, disruption of hormone homeostasis, and molecular and epigenetic changes in target tissue. Further work is needed to compare the PBDE toxic effects in rodents and humans.

6.
Biotech Histochem ; 93(6): 463-470, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29693452

RESUMO

Many types of aflatoxin cause problems for both public and animal health. Aflatoxin B1 (AFB1) is the most toxic and commonly encountered fungal toxin that appears in poultry feed and in feeds stored under unsuitable conditions. AFB1 decreases feed quality, egg production and fertility of hatching eggs. Also, AFB1 alters the development of embryos by infecting eggs. We investigated using sequence analysis the changes caused by different concentrations of AFB1 on the promoter sequences of the growth hormone regulated gene-1 (GHRG-1) in chick embryo at 13, 17, 19 and 21 days incubation. DNA isolated from the liver of chick embryos treated with different concentrations of AFB1 was separated using agarose gel electrophoresis to detect apoptosis, and DNA interaction with AFB1 was investigated using plasmids to detect changes in electrophoretic mobility and their effects on DNA. Base changes of the promoter sequences of GHRG-1 in 5 ng/egg, 15 ng/egg and 40 ng/egg doses of AFB1 were increased on day 19 compared to base changes of the same AFB1 doses on day 13. We also found that AFB at different concentrations changed the mobility of DNA by binding to it, and that high doses of AFB1 destroyed DNA. The DNA interaction study using plasmid demonstrated that AFB1 at high doses was bound to plasmid DNA, slowed its mobility and inhibited restriction cuts.


Assuntos
Aflatoxina B1/farmacologia , DNA/efeitos dos fármacos , Hormônio do Crescimento/efeitos dos fármacos , Fígado/efeitos dos fármacos , Ração Animal , Animais , Embrião de Galinha , Galinhas , DNA/metabolismo , Hormônio Liberador de Hormônio do Crescimento/efeitos dos fármacos , Hormônio Liberador de Hormônio do Crescimento/metabolismo , Fígado/embriologia
7.
Clin Exp Obstet Gynecol ; 44(3): 379-383, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29949277

RESUMO

PURPOSE: To examine the interobserver variability for fetal biometry parameters and to investigate whether this variability affects the second-trimester maternal serum screening test (STMSS) results. MATERIALS AND METHODS: A total of 60 singleton pregnancies who were scheduled for STMSS were investigated. Two experienced sonographers performed all examinations at the same visit. The risk calclations of screening were performed according to the each operator's biometric measurements separately. Interobserver variability in measurements of fetal biometrics and the effect of this interobserver variability on the screening results were assessed. RESULTS: inter-observer reliability for biparietal diameter (BPD) and femur length (FL) were 0.904 and 0.888 (p < 0.00 1), respectively. interobserver reliability coefficients for trisomy 21, trisomy 13/18, and neural tube defect were 0.887, 0.999, and 0.920 (p < 0.0001), respectively. CONCLUSION: The present results demonstrate that the interobserver reliability and agreement of ultrasound measurements of fetal biometry in cases of routine prenatal screening are highly reliable.


Assuntos
Biometria , Síndrome de Down/diagnóstico , Ultrassonografia Pré-Natal , Adulto , Feminino , Feto , Idade Gestacional , Humanos , Variações Dependentes do Observador , Gravidez , Segundo Trimestre da Gravidez , Diagnóstico Pré-Natal , Reprodutibilidade dos Testes , Trissomia , Adulto Jovem
8.
J Viral Hepat ; 24(6): 496-505, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27925346

RESUMO

Hepatitis C virus (HCV) is easily spread among those who share drug injection equipment. Due to the ease of contraction and growing prevalence of HCV in Eastern Europe, the aims of this study focused on describing risky injection practices as well as the prevalence of HCV, HIV and hepatitis B virus (HBV) among people who inject drugs (PWID) who were admitted to public and private drug treatment centres in Turkey from 2012 to 2013. Other aims included identifying correlates of needle sharing and HCV infection. Of the 4694 inpatients who ever injected drugs and the 3914 who injected in the past 30 days, nearly all (98%) reported heroin as their drug of choice, the vast majority reported ever sharing a needle (73.4% and 79.3%), and the mean age at first injection was 23 years. Of current PWID, 51.9% were HCV-positive, 5.9% were HBV-positive and only 0.34% of lifetime PWID were HIV-positive. Predictors of increased needle sharing include younger age, being unemployed, having lesser education and reporting heroin as a drug of choice. Significant predictors of HCV infection included being 40 years or older, receiving treatment in the Mediterranean region of Turkey, reporting heroin as a primary substance, a longer duration of drug use and sharing needles. With this information, it is essential to improve access to clean injection equipment in Turkey, to focus on improving education on clean injection practices and to enhance efforts in testing and treating HCV-positive PWID.


Assuntos
Hepatite B/epidemiologia , Hepatite C/epidemiologia , Uso Comum de Agulhas e Seringas/efeitos adversos , Abuso de Substâncias por Via Intravenosa/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Europa Oriental , Feminino , Infecções por HIV/epidemiologia , Humanos , Pacientes Internados , Masculino , Região do Mediterrâneo , Pessoa de Meia-Idade , Turquia/epidemiologia , Adulto Jovem
9.
Hum Exp Toxicol ; 34(8): 787-95, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25394903

RESUMO

Agomelatine is a potent agonist at melatonergic 1 and 2 (MT1 and MT2) receptors and an antagonist at serotonin-2C (5HT-2C) receptors. It was suggested that psychotropic effects of agomelatine is associated with its melatonergic and serotonergic effects. In this study, we aimed to evaluate the effects of agomelatine alone or in combination with ritanserin (5HT-2A/2C antagonist) on memory and learning. Male Balb-C mice (25-30 g) were used, and all drugs and saline were administrated by intraperitoneal (i.p.) route 30 min prior to evaluating retention time. Whilst agomelatine was administered at the doses of 1, 10 and 30 mg/kg, ritanserin was administered at the doses of 0.1, 1 and 10 mg/kg. To evaluate memory function, passive avoidance test was used. On the first day, acquisition time and on the second day (after 24h), retention time of mice were recorded. To evaluate the synergistic activity, only the least doses of agomelatine and ritanserine were used, that is, 1 and 0.1 mg/kg, respectively. Scopolamine (1 mg/kg) was used as a reference drug, so it was combined with drug groups. Our results show that 5HT-2A/2C receptor antagonist ritanserin (1 and 4 mg/kg, i.p.) and agomelatine (10 and 30 mg/kg, i.p.) improve memory deficit induced by scopolamine, whilst a synergistic interaction is observed between ritanserin and agomelatine (0.1 mg/kg and 1 mg/kg, i.p., respectively) when they were administered at their ineffective doses. According to our findings, we concluded that agomelatine improves memory deficit and thus improves the effect of agomelatine arises from its 5HT-2C receptor antagonist activity.


Assuntos
Acetamidas/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Ritanserina/farmacologia , Acetamidas/administração & dosagem , Animais , Sinergismo Farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ritanserina/administração & dosagem
10.
Clin Rehabil ; 29(6): 525-37, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25142280

RESUMO

OBJECTIVE: To determine whether symptoms of urinary incontinence is reduced by pelvic floor muscle training, to determine whether urinary incontinence can be totally eliminated by strengthening the pelvic floor muscle to grade 5 on the Oxford scale. DESIGN: Prospective randomized controlled clinical trial. SETTING: Outpatient urogynecology department. SUBJECTS: One hundred thirty cases with stress and mixed urinary incontinence. INTERVENTION: All participants were randomly allocated to the pelvic floor muscle training group or control group. A 12-week home based exercise program, prescribed individually, was performed by the pelvic floor muscle training group. MAIN MEASURES: Urinary incontinence symptoms (Incontinence Impact Questionnaire-7, Urogenital Distress Inventory-6, bladder diary, stop test and pad test) were assessed, and the pelvic floor muscle strength was measured for (PERFECT testing, perineometric and ultrasound) all participants before and after 12 weeks of treatment. RESULTS: The pelvic floor muscle training group had significant improvement in their symptoms of urinary incontinence (P=0.001) and an increase in pelvic floor muscle strength (P=0.001, by the dependent t test) compared with the control group. All the symptoms of urinary incontinence were significantly decreased in the patients that had reached pelvic floor muscle strength of grade 5 and continued the pelvic floor muscle training (P<0.05). CONCLUSION: The study demonstrated that pelvic floor muscle training is effective in reducing the symptoms of stress and mixed urinary incontinence and in increasing pelvic floor muscle strength.


Assuntos
Terapia por Exercício , Diafragma da Pelve , Incontinência Urinária/terapia , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Método Simples-Cego , Avaliação de Sintomas , Resultado do Tratamento
11.
J Crohns Colitis ; 8(5): 401-8, 2014 05.
Artigo em Inglês | MEDLINE | ID: mdl-24230968

RESUMO

BACKGROUND: Coping is an integral part of adjustment for patients with Inflammatory Bowel Disease but has not been well described in the literature. This study explored the relationship between coping, perceived health competence, patient preference for involvement in their treatment, depression and quality of life, particularly among patients with inactive disease (in remission). METHODS: Subjects (n=70) with active and inactive IBD completed questionnaires, including the Inflammatory Bowel Disease Quality of Life Questionnaire, Beck Depression Inventory, Perceived Health Competence Scale and the Coping Inventory for Stressful Situations. The Harvey Bradshaw Index measured disease activity. RESULTS: Patients with inactive IBD demonstrated significantly more interest in participating in their treatment (p<.05), more perceived health competence (p=.001), less depressive symptoms (p<.001), more task oriented coping (p=.02), and better quality of life than those with active disease. Only Task Oriented Coping was significantly negatively associated with the number of flares among inactive patients (p<.001). Patient preference for participation in treatment was inversely associated with Avoidance (p=.005), Distraction (p=.008), and Social Diversion (p=.008) coping among inactive patients. CONCLUSION: Among patients in remission, those who expressed a greater interest in treatment participation were also less likely to practice maladaptive coping. Our data demonstrate that a more active coping style may be associated with improved health outcome. Compared to patients with active disease, patients in remission are more likely to employ task oriented coping, demonstrate a higher interest in treatment participation, report greater perceived control of their health, and exhibit less depression symptoms. Our findings may increase awareness of the importance of identifying coping strategies for IBD patients, including those in remission.


Assuntos
Adaptação Psicológica , Doenças Inflamatórias Intestinais/psicologia , Competência Mental/psicologia , Participação do Paciente/psicologia , Adolescente , Adulto , Idoso , Depressão/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Apoio Social , Estresse Psicológico/psicologia , Inquéritos e Questionários
12.
J Pediatr Endocrinol Metab ; 22(12): 1159-62, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20333876

RESUMO

Pompe's disease is a glycogen storage disease (type II) characterized by inherited autosomal recessive transmission. A 4 month-old girl presented with rapid disease progression, exhibiting severe hypotonia, and hypertrophic cardiomyopathy, progressing to respiratory failure by the age of 9 months. Despite its low incidence, infantile Pompe's disease is lethal. The availability of an effective treatment has created an urgent need to improve knowledge and early diagnosis of this disease. The clinical response is variable from patient to patient with a better effect in patients enrolled earlier. The only clinically available therapy for Pompe's disease is enzyme replacement therapy (ERT). Gene therapy is still not available for Pompe's disease due to lack of suitable vectors for long-term and tissue-specific expression. Recombinant human alpha-glucosidase remains a hope for patients.


Assuntos
Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/etiologia , Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II/complicações , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , alfa-Glucosidases/administração & dosagem , Evolução Fatal , Feminino , Humanos , Lactente , Proteínas Recombinantes/administração & dosagem , Índice de Gravidade de Doença
13.
Public Health ; 121(5): 349-56, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17337284

RESUMO

OBJECTIVES: The purpose of this study was to develop a more detailed understanding of the characteristics of occasional smokers, and how the characteristics of occasional smokers differ from those of daily smokers. This information can then be used in youth smoking programmes to better address these differences in a manner that would target appropriate youth with appropriate cessation methods. METHODS: A questionnaire was administered to 976 university students, aged between 18 and 25 years, in Ankara, Turkey. The topics covered included age, sex and tobacco use characteristics. Daily and occasional smokers were defined according to traditional definitions of smoking. RESULTS: Among the 976 students surveyed, 482 (49.4%) reported being active smokers. Among these smokers, 199 (41.3%) were classified as occasional smokers and 283 (58.7%) were daily smokers using the traditional definitions of smoking. Many of the active smokers had relatives or friends who also smoked, specifically, 46.5% had a father who smokes, 13.3% had a mother who smokes, 26.8% had an older brother or sister who smokes, and 69.7% had two or more close friends who smoke. Although more than 51.3% of smokers planned on quitting smoking, only 26.1% had previously tried to quit smoking but 64.7% believed they could successfully quit. Daily smokers reported that they made fewer attempts to quit smoking than occasional smokers. More often than occasional smokers, daily smokers reported that they smoke because they like the image, they are addicted, smoking relieves stress and/or their friends smoke. Occasional smokers reported that they smoke less at home or at the university than in other places, and smoke more often with friends than when alone or with family members. This pattern is encouraged by the family structure in Turkish society, where smoking by adolescents at home in the presence of family members is frowned upon. CONCLUSIONS: This study demonstrates substantial differences between occasional and daily smokers. If effective future smoking prevention and cessation programmes that target youth are going to be developed, data like those gathered in this study are critical. Basic information regarding cigarette consumption patterns, while important, is insufficient to understand behaviour and key factors that trigger smoking among the youth population.


Assuntos
Comportamentos Relacionados com a Saúde , Conhecimentos, Atitudes e Prática em Saúde , Fumar/epidemiologia , Adolescente , Serviços de Saúde do Adolescente , Adulto , Fatores Etários , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Fatores de Risco , Assunção de Riscos , Estudantes/psicologia , Inquéritos e Questionários , Turquia/epidemiologia
14.
J Pharmacol Exp Ther ; 306(1): 13-28, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12815011

RESUMO

Using monolayers of intestinal (Caco-2) cells, we showed that oxidants disrupt the microtubule cytoskeleton and barrier integrity; epidermal growth factor (EGF) was protective via stabilization of the microtubules. Because proinflammatory conditions activate nuclear factor-kappaB (NF-kappaB), we hypothesized that oxidants disrupt barrier integrity through activation of NF-kappaB and that EGF protects by suppressing NF-kappaB. Parental cells were pretreated with EGF or NF-kappaB or inhibitory kappaBalpha (I-kappaBalpha) modulators. Other cells were stably transfected with varying levels of a dominant negative mutant for the NF-kappaB inhibitor I-kappaBalpha. Both types of cells were grown as monolayers and then exposed to oxidant (H2O2). We then monitored monolayer barrier integrity (permeability), stability of the microtubule cytoskeleton (confocal microscopy, immunoblotting), intracellular levels of the I-kappaBalpha (immunoblotting), translocation, and activity of NF-kappaB (immunoblotting, sensitive enzyme-linked immunosorbent assay). Monolayers were also fractionated and processed to assess alterations in 1) polymerized tubulin (S2; an index of cytoskeletal integrity) and 2) monomeric tubulin (S1; an index of disassembly) (polyacrylamide gel electrophoresis fractionation and immunoblotting). We found the following: 1) Oxidants caused I-kappaBalpha degradation, NF-kappaB translocation, NF-kappaB (p50 and p65 subunits) activation, tubulin disassembly ( upward arrow S1, downward arrow S2), microtubule architectural instability, and barrier disruption. I-kappaBalpha stabilizers and NF-kappaB inhibitors [e.g., carbobenzyloxy-leuleu-leucinol (MG-132), lactacystin] suppressed oxidants injurious effects. 2) EGF (10 ng/ml) stabilized I-kappaBalpha and prevented both NF-kappaB translocation and activation while protecting monolayers against oxidants. 3) In stably transfected cells, transfection-induced stabilization of I-kappaBalpha by itself led to EGF-like protective effects. In these mutant cells, protection was not potentiated by EGF (10 ng/ml). Conclusions are 1) oxidants induce disruption of the cytoskeleton and intestinal barrier integrity, in part, through I-kappaBalpha degradation and subsequent NF-kappaB activation, 2) I-kappaBalpha stabilization is by itself protective, mimicking EGF, and 3) EGF protects cell monolayers through I-kappaBalpha stabilization and NF-kappaB inactivation. To our knowledge, this is the first report that NF-kappaB can affect the dynamics of cytoskeletal assembly and intestinal barrier integrity.


Assuntos
Citoesqueleto/metabolismo , Fator de Crescimento Epidérmico/fisiologia , Mucosa Intestinal/fisiologia , Microtúbulos/metabolismo , NF-kappa B/metabolismo , Transporte Biológico , Células CACO-2 , Citoproteção/fisiologia , Citoesqueleto/efeitos dos fármacos , Interações Medicamentosas , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Microtúbulos/efeitos dos fármacos , Inibidor de NF-kappaB alfa , Oxidantes/farmacologia , Transfecção
15.
Gut ; 52(5): 720-8, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12692059

RESUMO

BACKGROUND: Overproduction of colonic oxidants contributes to mucosal injury in inflammatory bowel disease (IBD) but the mechanisms are unclear. Our recent findings using monolayers of intestinal cells suggest that the mechanism could be oxidant induced damage to cytoskeletal proteins. However, oxidants and oxidative damage have not been well characterised in IBD mucosa. AIMS: To determine whether there are increases in oxidants and in tissue and cytoskeletal protein oxidation in IBD mucosa. METHODS: We measured nitric oxide (NO) and markers of oxidative injury (carbonylation and nitrotyrosination) to tissue and cytoskeletal proteins in colonic mucosa from IBD patients (ulcerative colitis, Crohn's disease, specific colitis) and controls. Outcomes were correlated with IBD severity score. RESULTS: Inflamed mucosa showed the greatest increases in oxidants and oxidative damage. Smaller but still significant increases were seen in normal appearing mucosa of patients with active and inactive IBD. Tissue NO levels correlated with oxidative damage. Actin was markedly (>50%) carbonylated and nitrated in inflamed tissues of active IBD, less so in normal appearing tissues. Tubulin carbonylation occurred in parallel; tubulin nitration was not observed. NO and all measures of oxidative damage in tissue and cytoskeletal proteins in the mucosa correlated with IBD severity. Disruption of the actin cytoarchitecture was primarily within the epithelial cells and paracellular area. CONCLUSIONS: Oxidant levels increase in IBD along with oxidation of tissue and cytoskeletal proteins. Oxidative injury correlated with disease severity but is also present in substantial amounts in normal appearing mucosa of IBD patients, suggesting that oxidative injury does not necessarily lead to tissue injury and is not entirely a consequence of tissue injury. Marked actin oxidation (>50%)-which appears to result from cumulative oxidative damage-was only seen in inflamed mucosa, suggesting that oxidant induced cytoskeletal disruption is required for tissue injury, mucosal disruption, and IBD flare up.


Assuntos
Colo/metabolismo , Doenças Funcionais do Colo/metabolismo , Proteínas do Citoesqueleto/metabolismo , Óxido Nítrico/análise , Tirosina/análogos & derivados , Actinas/análise , Adulto , Western Blotting/métodos , Colite Ulcerativa/metabolismo , Doença de Crohn/metabolismo , Feminino , Radicais Livres/análise , Humanos , Immunoblotting/métodos , Mucosa Intestinal/metabolismo , Medições Luminescentes , Masculino , Oxirredução , Tubulina (Proteína)/análise , Tirosina/análise
16.
Dig Dis Sci ; 47(6): 1342-8, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12064811

RESUMO

Rebamipide protects gastrointestinal mucosal integrity against reactive oxygen species (ROS). The effect of rebamipide on the capability of PMNs to produce ROS in the presence of plasma and rectal dialysates (RD) of control and ulcerative colitis (UC) subjects was evaluated. We recruited six healthy volunteers for obtaining PMNs, control plasma, and control RD and six patients with inactive UC for obtaining plasma and RD. PMNs were activated using fMLP, and ROS was measured by fluorescent microplate assay (DCFD). Rebamipide significantly inhibited the neutrophil respiratory burst by 45%. Plasma from both control subjects and UC patients significantly blunted the fMLP-induced respiratory burst. However, the plasma of the UC patients was significantly less inhibitory than the plasma of control subjects. RD from control subjects significantly blunted the fMLP-induced respiratory burst while, RD from patients with UC did not. Rebamipide maintained its antioxidant effects in the presence of plasma or RD obtained from both controls and UC patients. In conclusion, partial loss of the inhibitory effects of plasma and RD in patients with UC may contribute to oxidative-induced tissue damage in UC and rebamipide antioxidant properties were not hampered by the biological milieu of patients with UC.


Assuntos
Alanina/análogos & derivados , Alanina/farmacologia , Antioxidantes/farmacologia , Colite Ulcerativa/fisiopatologia , Neutrófilos/metabolismo , Quinolonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Explosão Respiratória/efeitos dos fármacos , Colite Ulcerativa/sangue , Humanos
17.
Am J Gastroenterol ; 96(4): 1080-4, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11316150

RESUMO

OBJECTIVE: Chronic radiation proctitis, a common sequelae of pelvic radiation, is characterized by obliteration of the submucosal vasculature with subsequent ischemia and reperfusion injury. Oxidative stress is thought to be a major mechanism in radiation proctitis. Therefore, antioxidants (vitamins E and C) may be beneficial. METHODS: Twenty consecutive symptomatic outpatients with endoscopically documented radiation proctitis seen in a single gastroenterology clinic were given a combination of vitamin E (400 IU tid) and vitamin C (500 mg tid). Previous radiation therapy was given for prostatic (n = 10) or gynecological (n = 10) malignancies. These patients presented with one or more of the following symptoms: rectal bleeding, rectal pain, diarrhea, or fecal urgency. Using a questionnaire, these symptoms were rated by the patients in terms of their severity (grade 0-4) and frequency (grade 0-4) before and after treatment with vitamins E and C. A symptom index was calculated by the addition of the severity and frequency scores (8 = most symptomatic). The lifestyle impact of the symptoms was also assessed by questionnaire grading from 0 (no effect on daily activity) to 4 (afraid to leave home). Among these 20 patients, 10 patients who received vitamins E and C for 1 yr were assessed again to determine whether their initial responses were sustained. RESULTS: There was a significant (p < 0.05; Wilcoxon rank) improvement in the symptom index (before treatment vs after treatment with vitamins E and C) for bleeding (median score: 4 vs 0), diarrhea (median score: 5 vs 0), and urgency (median score: 6 vs 3). Patients with rectal pain did not improve significantly. Bleeding resolved in four of 11 patients, diarrhea resolved in eight of 16 patients, fecal urgency resolved in three of 16 patients, and rectal pain resolved in two of six patients. Lifestyle improved in 13 patients, including seven patients who reported a return to normal. Two of the patients with no improvement in their daily symptoms also had radiation ileitis. All 10 patients who underwent a second follow-up interview reported sustained improvement in their symptoms 1 yr later. CONCLUSION: A substantial number of patients with radiation proctitis seem to benefit from antioxidant therapy. A double-blind placebo-controlled trial is needed to confirm this open-labeled pilot study.


Assuntos
Antioxidantes/uso terapêutico , Ácido Ascórbico/uso terapêutico , Proctite/tratamento farmacológico , Proctite/etiologia , Lesões por Radiação/complicações , Lesões por Radiação/tratamento farmacológico , Vitamina E/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão
18.
Chest ; 119(4): 1222-41, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11296191

RESUMO

Mechanical ventilation (MV) can be lifesaving by maintaining gas exchange until the underlying disorders are corrected, but it is associated with numerous organ-system complications, which can significantly affect the outcome of critically ill patients. Like other organ systems, GI complications may be directly attributable to MV, but most are a reflection of the severity of the underlying disease that required intensive care. The interactions of the underlying critical illness and MV with the GI tract are complex and can manifest in a variety of clinical pictures. Incorporated in this review are discussions of the most prevalent GI complications associated with MV, and current diagnosis and management of these problems.


Assuntos
Gastroenteropatias/etiologia , Respiração Artificial/efeitos adversos , Colecistite/etiologia , Estado Terminal , Diarreia/etiologia , Esofagite/etiologia , Gastroenteropatias/diagnóstico , Gastroenteropatias/terapia , Motilidade Gastrointestinal , Humanos , Respiração com Pressão Positiva/efeitos adversos , Fatores de Risco , Circulação Esplâncnica , Úlcera Gástrica/etiologia , Úlcera Gástrica/prevenção & controle , Estresse Fisiológico/complicações
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