RESUMO
In this study, a biological conduit, consisting of an adipocyte-derived mesenchymal stem cell (AdMSCs) sheet and amniotic membrane (AM), was designed for the reconstruction of peripheral nerve defects. To evaluate the effect of the produced conduit on neural regeneration, a 10-mm sciatic nerve defect was created in rats, and experiments were carried out on six groups, i.e., sham control group (SC), negative control group (NC), nerve autograft group (NG), the biological conduit (AdMSCs + AM) group, the commercial PGA tube conduit (PGA) group, and the conduit only consisting of AM (AM) group. The effects of different nerve repair methods on the peripheral nerve and gastrocnemius muscle were evaluated by functional, histological, and immunohistochemical tests. When the number of myelinated axons was compared between the groups of AdMSCs + AM and PGA, it was higher in the AdMSCs + AM group (p < 0.05). The percentage of gastrocnemius collagen bundle area of AdMSCs + AM group was found to be statistically lower than the PGA group (p < 0.05). The muscle fiber diameter of AdMSCs + AM group was lower than that of the NG group, but significantly higher than that of the PGA group and the AM group (p < 0.001). Muscle weight index was significantly higher in the AdMSCs + AM group compared to the PGA group (p < 0.05). It was observed that nerve regeneration was faster in the AdMSCs + AM group, and there was an earlier improvement in pin-prick score and sciatic functional index compared to the PGA group and the AM group. In conclusion, the biological conduit prepared from the AdMSCs sheet and AM is regarded as a new biological conduit that can be used as an alternative treatment method to nerve autograft in clinical applications.
Assuntos
Células-Tronco Mesenquimais , Tecido Nervoso , Humanos , Ratos , Animais , Âmnio , Nervo Isquiático/cirurgia , Nervo Isquiático/transplante , Modelos Animais de Doenças , Regeneração Nervosa/fisiologiaRESUMO
Doxorubicin (DOXO) may cause serious cardiotoxic effects that limit its use as an antineoplastic agent. We aimed to evaluate the protective role of taurine (TAU), a beta amino acid with antioxidant activity, against DOXO-induced cardiotoxicity in a rat model. Thirty-one male Sprague-Dawley rats (300-400 g) were randomized into four groups: control (n = 7, intraperitoneal [ip] saline for 14 days), TAU (n = 8, 150 mg/kg body weight TAU ip for 14 days), DOXO (n = 8, 25 mg/kg body weight DOXO ip on 12th, 13th, and 14th days), and DOXO + TAU (n = 8, TAU for 14 days and DOXO on 12th, 13th, and 14th days). The left ventricular functions were evaluated on 15th day by echocardiography. The heart tissues were then excised for histological evaluation. In DOXO group, left ventricular ejection fraction (LVEF), fractional shortening (FS), and mitral lateral annulus (s') velocity were significantly lower, and the left ventricular end-diastolic and end-systolic diameters (LVEDD, LVESD) were significantly higher than control group (p < 0.05), indicating a significant deterioration in left ventricular functions. However, in comparison to DOXO group, LVESD, LVEDD, LVEF, FS, and s' were significantly improved in DOXO + TAU group (p < 0.05). On histological evaluation, contrary to the normal cellular structure of cardiomyocytes in control and TAU groups, DOXO group showed increased nuclear or cytoplasmic changes and infiltrative cell proliferation (p < 0.001), which were remarkably reduced in DOXO + TAU group (p < 0.001). TAU treatment has a protective effect against DOXO-induced cardiotoxicity on echocardiographical and histological evaluation. For common use of TAU to prevent DOXO-induced cardiotoxicity, our findings should be confirmed by clinical studies.
Assuntos
Antibióticos Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Cardiopatias/induzido quimicamente , Cardiopatias/prevenção & controle , Taurina/uso terapêutico , Animais , Cardiotoxicidade , Modelos Animais de Doenças , Ecocardiografia , Cardiopatias/diagnóstico por imagem , Cardiopatias/fisiopatologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
DNA polymerase V (pol V) of Escherichia coli is a translesion DNA polymerase responsible for most of the mutagenesis observed during the SOS response. Pol V is activated by transfer of a RecA subunit from the 3'-proximal end of a RecA nucleoprotein filament to form a functional complex called DNA polymerase V Mutasome (pol V Mut). We identify a RecA surface, defined by residues 112-117, that either directly interacts with or is in very close proximity to amino acid residues on two distinct surfaces of the UmuC subunit of pol V. One of these surfaces is uniquely prominent in the active pol V Mut. Several conformational states are populated in the inactive and active complexes of RecA with pol V. The RecA D112R and RecA D112R N113R double mutant proteins exhibit successively reduced capacity for pol V activation. The double mutant RecA is specifically defective in the ATP binding step of the activation pathway. Unlike the classic non-mutable RecA S117F (recA1730), the RecA D112R N113R variant exhibits no defect in filament formation on DNA and promotes all other RecA activities efficiently. An important pol V activation surface of RecA protein is thus centered in a region encompassing amino acid residues 112, 113, and 117, a surface exposed at the 3'-proximal end of a RecA filament. The same RecA surface is not utilized in the RecA activation of the homologous and highly mutagenic RumA'2B polymerase encoded by the integrating-conjugative element (ICE) R391, indicating a lack of structural conservation between the two systems. The RecA D112R N113R protein represents a new separation of function mutant, proficient in all RecA functions except SOS mutagenesis.
Assuntos
DNA Polimerase Dirigida por DNA/genética , Proteínas de Escherichia coli/genética , Recombinases Rec A/genética , Resposta SOS em Genética , Ativação Transcricional/genética , Trifosfato de Adenosina/genética , Sequência de Aminoácidos , Dano ao DNA , Replicação do DNA , DNA Polimerase Dirigida por DNA/metabolismo , Escherichia coli , Proteínas de Escherichia coli/metabolismo , Mutagênese/genética , Mutação , Nucleoproteínas/genética , Recombinases Rec A/metabolismoRESUMO
BACKGROUND: Erdosteine is a mucolytic agent with antioxidant and anti-inflammatory effects. We evaluated the protective effect of erdosteine pretreatment on oleic acid (OA)-induced acute lung injury. MATERIALS AND METHODS: Twenty-four male Wistar Albino rats were assigned to four treatments: control (oral saline + 50 µL intravenous [i.v.] saline), OA (oral saline + 50 µL i.v. OA), erdosteine (150 mg/kg oral erdosteine + 50 µL i.v. saline), and OA + erdosteine (150 mg/kg oral erdosteine + 50 µL i.v. OA). Four hours after OA injection, lung tissues were excised for biochemical and histopathologic evaluation. RESULTS: OA treatment increased lung weight and tissue malondialdehyde and protein carbonyl levels, but erdosteine pretreatment significantly suppressed these changes (0.57 ± 0.1 g, 3.27 ± 0.48 nmol/mg protein, and 33.57 ± 4.6 nmol/mg protein, respectively, for OA versus 0.36 ± 0.02 g, 1.84 ± 0.15 nmol/mg protein, and 22.10 ± 2.55 nmol/mg protein, respectively, for OA + erdosteine; P < 0.05 for all). Erdosteine pretreatment increased the activities of the antioxidant enzymes, catalase, and glutathione peroxidase (0.16 ± 0.03 k/g and 0.3 ± 0.01 U/mg protein, respectively, for OA versus 0.33 ± 0.05 k/g and 0.34 ± 0.01 U/mg protein, respectively, for OA + erdosteine; P < 0.05 for both). Erdosteine pretreatment also significantly decreased the median numbers of intra-alveolar macrophages and intra-alveolar and interstitial neutrophils (29.0, 17.0, and 15.0, respectively, for OA versus 12.5, 4.0, and 6.5, respectively, for OA + erdosteine; P < 0.001 for all). CONCLUSIONS: Erdosteine pretreatment increased the activities of antioxidant enzymes and decreased macrophage and neutrophil accumulation, thereby ameliorating the inflammatory effects of OA treatment. Erdosteine pretreatment prevents OA-induced oxidative stress and inflammation and protects the lung tissue against acute lung injury.
Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Expectorantes/uso terapêutico , Ácido Oleico/efeitos adversos , Substâncias Protetoras/uso terapêutico , Tioglicolatos/uso terapêutico , Tiofenos/uso terapêutico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/metabolismo , Administração Oral , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Esquema de Medicação , Macrófagos Alveolares/metabolismo , Masculino , Neutrófilos/metabolismo , Distribuição Aleatória , Ratos , Ratos WistarRESUMO
Previous studies have shown that 2-deoxy-d-glucose (2-DG) increases gastric motility via the vagus nerve, but the underlying mechanism remains elusive. Since nitric oxide (NO) is involved in gastric motility, a possible interplay between 2-DG and NO can be suggested. In the present study, Wistar rats (250-350 g) of both sexes were intravenously injected with 2-DG (200 mg/kg), and the effects of the intravenous injection of the nitric oxide synthase (NOS) inhibitors; nitro-l-arginine methyl ester (l-NAME, 10 mg/kg) and Nω -nitro-l-arginine (l-NNA, 10 mg/kg) were investigated. Animals were anaesthetized and cannulated for intravenous drug injections while the left vagal nerve was electrically stimulated (0.1-10 Hz, 0.5 ms duration, 12 V, for 60 seconds), and intragastric pressure and gastric motility changes were monitored using a latex gastric balloon. 2-DG increased the mean intragastric pressure (baseline, 5.0±0.4 cmH2 O; after 2-DG, 14.4±1.5 cmH2 O; P=.0156) and significantly increased the gastric motility index, while NOS inhibitors significantly attenuated both parameters. However, pretreatment with NOS inhibitors significantly augmented the gastric responses to peripheral electrical vagal stimulation. These results suggest that NO plays an excitatory role in gastric responsiveness to 2-DG and that this function may be effected in the central nervous system.
Assuntos
Desoxiglucose/farmacologia , Motilidade Gastrointestinal/efeitos dos fármacos , Óxido Nítrico/metabolismo , Estômago/efeitos dos fármacos , Estômago/fisiologia , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Feminino , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Nitroarginina/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Estômago/inervação , Estimulação do Nervo VagoRESUMO
AIM: Empagliflozin (EMPA) is a sodium-glucose transporter-2 inhibitor used in the treatment of type 2 diabetes and has positive effects on cardiovascular outcomes. Amitriptyline (AMT) can be used in many clinical indications but leads to cardiotoxicity by causing QT prolongation. Our aim in this study was to determine how the effects of the concomitant use of empagliflozin and amitriptyline, which have been shown to have effects on sodium and calcium metabolism in cardiomyocytes, would cause an effect on QT and QTc intervals in clinical practice. METHODS: Twenty-four male Wistar albino rats were randomised into four groups. The control group received only physiological serum (1 ml) via orogastric gavage (OG). The EMPA group received empagliflozin (10 mg/kg) via OG. The AMT group received amitriptyline (100 mg/kg) via OG. The AMT + EMPA group (n = 6) received amitriptyline (100 mg/kg) and empagliflozin (10 mg/kg). Under anaesthesia, QT and QTc intervals were measured at baseline, and in the first and second hours. RESULTS: In the AMT group, QT intervals and QTc values were found to be statistically longer than in the control group (p ≤ 0.001). Empagliflozin significantly ameliorated amitriptyline-induced QT and QTc prolongation. In the AMT + EMPA group, QT and QTc intervals were significantly lower compared to that in the AMT group (p < 0.01). CONCLUSION: In this study, we determined that empagliflozin significantly ameliorated amitriptyline-induced QT and QTc prolongation. This effect was probably due to the opposite effects of these two agents in the intracellular calcium balance. With more clinical trials, the routine use of empagliflozin may be suggested to prevent QT and QTc prolongation in diabetic patients receiving amitriptyline.
RESUMO
BACKGROUND: Doxorubicin (dox) is a chemotherapeutic agent widely used against various tumors. However, the clinical use of this agent is limited due to various organ toxicities. Taurine is an intracellular free ß-amino acid with antioxidant properties. The present study investigated the protective mechanism of taurine on dox-induced hepatotoxicity. METHODS: In total, 31 male Sprague-Dawley rats were used in the study. The control group received intraperitoneal (i.p.) 0.9% NaCl alone for 14 days; the taurine (Tau) group received i.p. taurine 150 mg/kg body weight/day for 14 days; the dox group received dox on days 12, 13, and 14 at a cumulative dose of 25 mg/kg body weight/3 days; and the tau+dox group received taurine and dox together at the same dose and through the same route. On day 15, biochemical evaluations were performed on blood samples taken from the left ventricle followed by histological examinations on liver samples. RESULTS: Dox was found to increase liver function enzymes and tissue protein carbonyl levels, causing congestion and tissue damage, thereby leading to dysfunction. Tau was found to histologically preserve the liver morphology without showing any corrective effect on oxidative stress parameters. These findings suggest that the membrane-stabilizing effect of taurine may be more effective than its radical scavenging activity in preventing dox-induced toxicity. CONCLUSION: Taurine can prevent doxorubicin-induced hepatotoxicity through non-antioxidant pathways.
RESUMO
Empagliflozin (EMPA) is a SGLT-2 inhibitor that has positive effects on cardiovascular outcomes. In this study, we aim to evaluate the possible protective effects of EMPA against doxorubicin (DOX)-induced acute cardiotoxicity. Non-diabetic Sprague-Dawley rats were randomized into four groups. The control group received serum physiologic (1 ml), the EMPA group received EMPA, the DOX group was administered cumulatively 18 mg/kg body weight DOX. The DOX+EMPA group was administered DOX and EMPA. In the DOX group, LVDED (P < 0.05) and LVSED (P < 0.01), QTc interval (P < 0.001), the ratio of karyolysis and karyorrhexis (P < 0.001) and infiltrative cell proliferation (P < 0.001) were found to be higher than; EF, FS and normal cell morphology were lower than the control group (P < 0.001). In the DOX+EMPA group, LVEDD (P < 0.05) and LVESD (P < 0.01) values, QTc interval (P < 0.001), karyolysis and karyorrhexis ratios (P < 0.001) and infiltrative cell proliferation were lower (P < 0.01); normal cell morphology and EF were higher compared to the DOX group (P < 0.001). Our results showed that empagliflozin significantly ameliorated DOX-induced acute cardiotoxicity.
Assuntos
Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Cardiopatias/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Cardiotoxicidade , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Doxorrubicina , Cardiopatias/induzido quimicamente , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/ultraestrutura , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/ultraestrutura , Ratos Sprague-DawleyRESUMO
Although the bundle-forming pilus (BFP) of enteropathogenic Escherichia coli (EPEC) mediates microcolony formation on epithelial cells, the adherence of BFP-deficient mutants is significantly abrogated, but the mutants are still adherent due to the presence of intimin and possibly other adhesins. In this study we investigated the contribution of the recently described E. coli common pilus (ECP) to the overall adherence properties of EPEC. We found that ECP and BFP structures can be simultaneously observed in the course (between zero time and 7 h during infection) of formation of localized adherence on cultured epithelial cells. These two pilus types colocalized at different levels of the microcolony topology, tethering the adhering bacteria. No evidence of BFP disappearance was found after prolonged infection. When expressed from a plasmid present in nonadherent E. coli HB101, ECP rendered this organism highly adherent at levels comparable to those of HB101 expressing the BFP. Purified ECP bound in a dose-dependent manner to epithelial cells, and the binding was blocked with anti-ECP antibodies, confirming that the pili possess adhesin properties. An ECP mutant showed only a modest reduction in adherence to cultured cells due to background expression levels of BFP and intimin. However, isogenic mutants not expressing EspA or BFP were significantly less adherent when the ecpA gene was also deleted. Furthermore, a DeltaespA DeltaecpA double mutant (unable to translocate Tir and to establish intimate adhesion) was at least 10-fold less adherent than the DeltaespA and DeltaecpA single mutants, even in the presence of BFP. A Delta bfp DeltaespA DeltaecpA triple mutant showed the least adherence compared to the wild type and all the isogenic mutant strains tested, suggesting that ECP plays a synergistic role in adherence. Our data indicate that ECP is an accessory factor that, in association with BFP and other adhesins, contributes to the multifactorial complex interaction of EPEC with host epithelial cells.
Assuntos
Aderência Bacteriana/fisiologia , Escherichia coli Enteropatogênica/metabolismo , Proteínas de Escherichia coli/fisiologia , Proteínas de Fímbrias/fisiologia , Fímbrias Bacterianas/metabolismo , Aderência Bacteriana/genética , Escherichia coli Enteropatogênica/genética , Escherichia coli Enteropatogênica/ultraestrutura , Células Epiteliais/microbiologia , Proteínas de Escherichia coli/genética , Proteínas de Fímbrias/genética , Fímbrias Bacterianas/genética , Citometria de Fluxo , Células HT29 , Células HeLa , Humanos , Microscopia Eletrônica de TransmissãoRESUMO
Expression of catecholamine biosynthesizing enzymes, tyrosine hydroxylase (TH) and dopamine beta hydroxylase (DbetaH) increase with age in the adrenal medulla, however, the underlying mechanisms are unclear. In the present study, we examined the effect of peripheral angiotensin II (AngII) on the expression of TH and DbetaH, in the adrenal medulla of young (6 mo) and old (23 mo) Fischer-344 rats. Saline or AngII (230 ng/kg/min sc) was infused for 3 days using osmotic minipumps. Adrenomedullary TH and DbetaH mRNA levels increased significantly with age, and while AngII reduced the expression of these enzymes in young animals, it had no such effect in the old animals. Neuropeptide Y (NPY), which is co-released with catecholamines in the adrenal medulla and stimulates the synthesis of TH and DbetaH, was also upregulated with age and downregulated in response to AngII in young rats. However, in the old animals, the already elevated NPY expression remained unchanged following AngII treatment. This data indicate that the hypertensive effect of peripheral AngII is compensated by an inhibition of adrenomedullary catecholamine biosynthesis in young animals, but this mechanism is impaired in senescence, potentially contributing to the age-related increase in catecholamine biosynthesis.
Assuntos
Medula Suprarrenal/enzimologia , Envelhecimento/fisiologia , Angiotensina II/farmacologia , Dopamina beta-Hidroxilase/biossíntese , Tirosina 3-Mono-Oxigenase/biossíntese , Medula Suprarrenal/efeitos dos fármacos , Animais , Dopamina beta-Hidroxilase/genética , Regulação para Baixo/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Masculino , Neuropeptídeo Y/biossíntese , Neuropeptídeo Y/genética , RNA Mensageiro/genética , Ratos , Ratos Endogâmicos F344 , Tirosina 3-Mono-Oxigenase/genéticaRESUMO
INTRODUCTION: Emotion dysregulation (ED) has long been recognized in clinical descriptions of attention-deficit hyperactivity disorder (ADHD), but a renewed interest in ED has advanced research on the overlap between the two entities. Autonomic reactivity (AR) is a neurobiological correlate of emotion regulation; however, the association between ADHD and AR remains unclear. Our aim was to explore the clinical differences, AR, and subjective emotional responses to visual emotional stimuli in ADHD children with and without ED. METHOD: School-aged ADHD children with (n = 28) and without (n = 20) ED, according to the definition of deficiency in emotional self-regulation (DESR), and healthy controls (n = 22) were interviewed by using the Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime version (K-SADS-PL) to screen frequent psychopathologies for these ages. All subjects were evaluated with Child Behavior Checklist 6-18 (CBCL), the Strengths and Difficulties Questionnaire (SDQ), the McMaster Family Assessment Device (FAD), the School-Age Temperament Inventory (SATI), and Conners' Parent Rating Scale (CPRS-48), which were completed by parents. To evaluate emotional responses, the International Affective Picture System (IAPS) and the subjective and physiological responses (electrodermal activity and heart rate reactivity) to selected pictures were examined. RESULTS: Regarding clinically distinctive features, the ADHD+ED group differed from the ADHD-ED and the control groups in terms of having higher temperamental negative reactivity, more oppositional/conduct problems, and lower prosocial behaviors. In the AR measures, children in the ADHD+ED group rated unpleasant stimuli as more negative, but they still had lower heart rate reactivity (HRR) than the ADHD-ED and control groups; moreover, unlike the two other groups, the ADHD+ED group showed no differences in HRR between different emotional stimuli. CONCLUSION: The presented findings are unique in terms of their ability to clinically and physiologically differentiate between ADHD children with and without ED.
Assuntos
Sintomas Afetivos/psicologia , Nível de Alerta/fisiologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Emoções/fisiologia , Resposta Galvânica da Pele/fisiologia , Frequência Cardíaca/fisiologia , Adolescente , Sintomas Afetivos/diagnóstico , Sintomas Afetivos/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Sistema Nervoso Autônomo/fisiopatologia , Criança , Correlação de Dados , Feminino , Humanos , Masculino , Reconhecimento Visual de Modelos/fisiologia , Valores de Referência , Temperamento/fisiologiaRESUMO
Exposure to sulfur dioxide (SO2) and cold increases especially in the winter. SO2 or cold exposure destroys the oxidant/antioxidant balance and increases lipid peroxidation. However, the effect of coexistence of both factors has not been studied yet. Therefore, we investigated the effect of SO2 and/or repeated short-term cold exposure on the oxidant-antioxidant status and the possible protective role of vitamin E in the cardiopulmonary tissues of mice. Swiss albino mice of both sexes were assigned to eight groups. Four groups were kept at room temperature, injected either with saline or vitamin E (100 mg/kg) in the presence or absence of SO2 exposure (10 ppm, 1 h/day, 30 days). The remaining four groups received the same protocol but were exposed to cold (4 +/- 1 degrees C, 1 h/days, 30 days) instead of room temperature. On day 30, the lung and heart tissues were removed for biochemical analysis. SO2 and cold coexposure increased lactate level in the lung, and elevated thiobarbituric acid-reactive substance (TBARS) and reduced glutathione levels in both tissues, while vitamin E treatment reversed TBARS increment predominantly in the lung. In conclusion, cold and SO2 coexposure exerts more deleterious effects in the cardiopulmonary tissues, while vitamin E treatment seems to be protective, particularly in the lung.
Assuntos
Poluentes Atmosféricos/toxicidade , Antioxidantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Dióxido de Silício/toxicidade , Vitamina E/farmacologia , Administração por Inalação , Animais , Temperatura Baixa/efeitos adversos , Quimioterapia Combinada , Feminino , Glutationa Peroxidase/metabolismo , Coração/efeitos dos fármacos , Injeções Intraperitoneais , Ácido Láctico/metabolismo , Peroxidação de Lipídeos/fisiologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Estresse Oxidativo/fisiologia , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Behçet's disease (BD) is a chronic recurrent systemic vasculitis of unknown cause. Thrombotic tendency is another characteristics of BD. While hemorheological changes play crucial role in thrombosis, erythrocyte deformability (ED), which is one of the main determinants of microcirculation and blood viscosity, has not been studied before in BD. ED was measured by the filtration method in 13 active BD patients diagnosed according to the criteria proposed by International Study Group for BD (ISG-BD) and in 13 age-, sex-, weight-, smoking habit-, and blood pressure-matched healthy controls. ED was decreased in active BD patients compared to the healthy control subjects. The median deformability indices (DIs) in BD patients and healthy controls were 3.19 and 2.08 (p<0.001), respectively. The decrease in ED may be one of the reasons for increased thrombotic tendency in BD. Alteration in ED possibly plays a crucial role in the etiopathogenesis of thrombotic complications in BD and thus may be a target for treatment. Drugs increasing ED, such as pentoxifylline, have already been shown to be beneficial in the treatment of BD. Therefore, we propose that the therapeutic mechanism underlying the beneficial effect of this drug in BD is likely to be the correction of impaired ED.
Assuntos
Síndrome de Behçet/sangue , Deformação Eritrocítica , Adulto , Síndrome de Behçet/complicações , Síndrome de Behçet/etiologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pentoxifilina/farmacologia , Trombose/etiologiaRESUMO
To evaluate the effects of hypercholesterolemia on the relaxation function of the urinary bladder, we examined the physiological mechanisms involved in the isoproterenol-induced relaxation in isolated detrusor strips in vitro and voiding behavior in vivo in rats. Adult male Sprague-Dawley rats were fed standard (control, N = 16) or 4 % cholesterol diet (hypercholesterolemia, N = 17) for 4 weeks. Concentration-response curves for isoproterenol-induced relaxations in carbachol-precontracted detrusor muscle strips were recorded. The contributions of ß2- and ß3-adrenoceptors and ATP-dependent and Ca(2+)-dependent potassium channels to the relaxation response were investigated by using selective adrenergic agonists salbutamol and BRL 37344 and specific potassium channel inhibitors glibenclamide and charybdotoxin, respectively. Cystometrography was performed to assess bladder function. Hypercholesterolemic rats had higher serum cholesterol and low- and high-density lipoprotein levels than the controls with no sign of atherosclerosis. Isoproterenol-induced relaxation was significantly enhanced in the hypercholesterolemia group. Preincubation with the M2 receptor antagonist attenuated the relaxation response in both groups. The relaxation responses to isoproterenol and salbutamol were similar in both groups, while BRL 37344 appeared to produce a greater relaxant effect in the hypercholesterolemic rats. Also, the inhibitory effects of potassium channel inhibitors on relaxation responses were comparable among the groups. The cystometric findings revealed that threshold and basal pressure values were higher in the hypercholesterolemia group compared with controls. We showed that hypercholesterolemia leads to greater relaxation responses to isoproterenol, appears to impair the braking function of M2 cholinergic receptors on adrenoceptor-induced relaxations in the isolated detrusor muscle, and affects the voiding function in rats.
Assuntos
Hipercolesterolemia/fisiopatologia , Relaxamento Muscular/fisiologia , Músculo Liso/fisiologia , Bexiga Urinária/fisiologia , Micção/fisiologia , Agonistas Adrenérgicos/farmacologia , Animais , Hipercolesterolemia/metabolismo , Técnicas In Vitro , Canais KATP/metabolismo , Lipídeos/sangue , Masculino , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio Cálcio-Ativados/metabolismo , Ratos Sprague-Dawley , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Micção/efeitos dos fármacosRESUMO
The elevated levels of circulating catecholamines (CAs) with age may be related to the increased expression of CA biosynthetic enzymes, tyrosine hydroxylase (TH) and dopamine beta hydroxylase (DbetaH) in the adrenal medulla of senescent compared with younger animals. Neuropeptide Y (NPY) is co-synthesized and co-released with CAs in the adrenal medulla. NPY inhibits the stimulated secretion of CAs, however, its role in regulation of the genes encoding CA biosynthetic enzymes is not clear. We hypothesized that NPY up-regulates TH, DbetaH and NPY expression in the adrenal medullae of young and old Fischer-344 rats. NPY increased mRNA expression of TH, DbetaH, NPY and also enhanced TH protein level in the adrenal medullae of young rats by 50%, 35%, 45% and by 20%, respectively. We also examined the effect of NPY on TH and NPY mRNA in the hypothalamus. Basal expression of TH mRNA was decreased in the hypothalamus with age. DNA binding activities of activator protein-1 and cAMP response element binding protein were also augmented only in the young by 140% and 125%, respectively. We conclude that NPY stimulates the CA biosynthetic pathway in the adrenal medulla and positive auto-regulation of NPY might be involved in this process. The stimulatory effect of NPY on adrenomedullary CA biosynthetic pathway is blunted with age.
Assuntos
Medula Suprarrenal/efeitos dos fármacos , Dopamina beta-Hidroxilase/biossíntese , Hipotálamo/efeitos dos fármacos , Neuropeptídeo Y/farmacologia , Tirosina 3-Mono-Oxigenase/biossíntese , Medula Suprarrenal/enzimologia , Fatores Etários , Animais , Catecolaminas/biossíntese , Enzimas/biossíntese , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/fisiologia , Hipotálamo/enzimologia , Masculino , RNA Mensageiro/biossíntese , Ratos , Ratos Endogâmicos F344RESUMO
Escherichia coli DNA polymerase V (pol V), a heterotrimeric complex composed of UmuD'2C, is marginally active. ATP and RecA play essential roles in the activation of pol V for DNA synthesis including translesion synthesis (TLS). We have established three features of the roles of ATP and RecA. (1) RecA-activated DNA polymerase V (pol V Mut), is a DNA-dependent ATPase; (2) bound ATP is required for DNA synthesis; (3) pol V Mut function is regulated by ATP, with ATP required to bind primer/template (p/t) DNA and ATP hydrolysis triggering dissociation from the DNA. Pol V Mut formed with an ATPase-deficient RecA E38K/K72R mutant hydrolyzes ATP rapidly, establishing the DNA-dependent ATPase as an intrinsic property of pol V Mut distinct from the ATP hydrolytic activity of RecA when bound to single-stranded (ss)DNA as a nucleoprotein filament (RecA*). No similar ATPase activity or autoregulatory mechanism has previously been found for a DNA polymerase.DOI: http://dx.doi.org/10.7554/eLife.02384.001.
Assuntos
Adenosina Trifosfatases/genética , DNA Polimerase Dirigida por DNA/genética , Proteínas de Escherichia coli/genética , Escherichia coli/genética , Regulação Bacteriana da Expressão Gênica , Adenosina Trifosfatases/metabolismo , DNA de Cadeia Simples/genética , DNA de Cadeia Simples/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , DNA Polimerase Dirigida por DNA/metabolismo , Proteínas de Escherichia coli/metabolismo , Hidrólise , Mutação , Nucleoproteínas/genética , Nucleoproteínas/metabolismo , Recombinases Rec A/genética , Recombinases Rec A/metabolismoRESUMO
Most of the anatomical, physiological and neurochemical gender-related differences in the brain occur prenatally. The sexual differences in the brain are affected by sex steroid hormones, which play important roles in the differentiation of neuroendocrine system and behavior. Testosterone, estrogen and dihydrotestosterone are the main steroid hormones responsible for the organization and sexual differentiation of brain structures during early development. The structural and behavioral differences in the female and male brains are observed in many animal species; however, these differences are variable between species. Animal and human (in vivo imaging and postmortem) studies on sex differences in the brain have shown many differences in the local distribution of the cortex, the gray-white matter ratio, corpus callosum, anterior commissure, hypothalamus, bed nucleus of the stria terminalis, limbic system and neurotransmitter systems. This review aims to evaluate the anatomical, physiological and neurochemical differences in the female and male brains and to assess the effect of prenatal exposure to sex steroid hormones on the developing brain.