Toxic phorbol esters from Chinese Tallow (Sapium sebiferum L.Roxb.)

Toxic phorbol esters from Chinese tallow stimulate protein kinase C. Toxicon25, 1129 – 1233, 1987. — Phorbol esters were isolated from the seeds of Chinese tallow (Sapium sebiferum L. Roxb.). These compounds were based on the tigliane nuclei, 4-deoxyphorbol, 12-deoxyphorbol and 4,20-dideoxy-5-hydroxyphorbol. The pro-inflammatory activity (id50) of the pure compounds was between 0.042 and 2.6 nmoles per ear. Protein kinase C activation assays were carried out on samples of enzyme purified from mammalian brain and the activities (Ka) were in the range 76 – 176 nM. The 4,20-dideoxy-5-hydroxy analogue was inactive in both tests. Chinese tallow, which is used as a substitute for linseed oil, may represent an industrial toxic hazard in terms of both pro-inflammatory and tumour-promoting effects.

Does domperidone, a D2-antagonist alter gastric emptying rates and appetite sensations in healthy adults with high-fat meal? A block-randomised, single-blind placebo-controlled study

BACKGROUND: Accelerated gastric emptying (GE) may lead to reduced satiation, increased food intake and is associated with obesity and type 2 diabetes. Domperidone is a dopamine 2 (D(2)) receptor antagonist with claims of gastrointestinal tract pro-kinetic activity. In humans, domperidone is used as an anti-emetic and treatment for gastrointestinal bloating and discomfort. AIM: To determine the effect of acute domperidone administration on GE rate and appetite sensations in healthy adults. METHODS: A single-blind block randomised placebo-controlled crossover study assessed 13 healthy adults. Subjects ingested 10 mg domperidone or placebo 30 min before a high-fat (HF) test meal. GE rate was determined using the (13)CO(2) octanoic acid breath test. Breath samples and subjective appetite ratings were collected in the fasted and during the 360 min postprandial period. RESULTS:Gastric emptying half-time was similar following placebo (254 ± 54 min) and 10 mg domperidone (236 ± 65 min). Domperidone did not change appetite sensations during the 360 min postprandial period (P > 0.05). CONCLUSIONS: In healthy adults, acute administration of 10 mg domperidone did not change GE or appetite sensations following a HF test meal.

Targeted activation of toll-like receptors: conjugation of a toll-like receptor 7 agonist to a monoclonal antibody maintains antigen binding and specificity

Therapeutic activation of Toll-like receptors (TLR) has potential for cancer immunotherapy, for augmenting the activity of anti-tumor monoclonal antibodies (mAbs), and for improved vaccine adjuvants. A previous attempt to specifically target TLR agonists to dendritic cells (DC) using mAbs failed because conjugation led to non-specific binding and mAbs lost specificity. We demonstrate here for the first time the successful conjugation of a small molecule TLR7 agonist to an anti-tumour mAb (the anti-hCD 20 rituximab) without compromising antigen specificity. The TLR7 agonist UC-1V150 was conjugated to rituximab using two conjugation methods and yield, molecular substitution ratio, retention of TLR7 activity and specificity of antigen binding were compared. Both conjugation methods produced rituximab-UC-1V150 conjugates with UC-1V150 : rituximab ratio ranging from 1:1 to 3:1 with drug loading quantified by UV spectroscopy and drug substitution ratio verified by MALDI TOF mass spectroscopy. The yield of purified conjugates varied with conjugation method, and dropped as low as 31% using a method previously described for conjugating UC-1V150 to proteins, where a bifunctional crosslinker was firstly reacted with rituximab, and secondly to the TLR7 agonist. We therefore developed a direct conjugation method by producing an amine-reactive UV active version of UC-1V150, termed NHS:UC-1V150. Direct conjugation with NHS:UC-1V150 was quick and simple and gave improved conjugate yields of 65-78%. Rituximab-UC-1V150 conjugates had the expected pro-inflammatory activity in vitro (EC50 28-53 nM) with a significantly increased activity over unconjugated UC-1V150 (EC50 547 nM). Antigen binding and specificity of the rituxuimab-UC-1V150 conjugates was retained, and after incubation with human peripheral blood leukocytes, all conjugates bound strongly only to CD20-expressing B cells whilst no non-specific binding to CD20-negative cells was observed. Selective targeting of Toll-like receptor activation directly within tumors or to DC is now feasible.

Phenylephrine promotes phosphorylation of Bad in cardiac myocytes through the extracellular signal-regulated kinases 1/2 and protein kinase A.

Studies in non-cardiomyocytic cells have shown that phosphorylation of the Bcl-2 family protein Bad on Ser-112, Ser-136 and Ser-155 decreases its pro-apoptotic activity. Both phenylephrine (100 microM) and the cell membrane-permeating cAMP analog, 8-(4-chlorophenylthio)-cAMP (100 microM), protected against 2-deoxy-D-glucose-induced apoptosis in neonatal rat cardiac myocytes as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). In cardiac myocytes, phenylephrine primarily stimulates the alpha-adrenoceptor, but, at high concentrations (100 microM), it also increases the activity of the cAMP-dependent protein kinase, protein kinase A (PKA) through the beta-adrenoceptor. Phenylephrine (100 microM) promoted rapid phosphorylation of Bad(Ser-112) and Bad(Ser-155), though we were unable to detect phosphorylation of Bad(Ser-136). Phosphorylation of Bad(Ser-112) was antagonized by either prazosin or propranolol, indicating that this phosphorylation required stimulation of both alpha(1)- and beta-adrenoceptors. Phosphorylation of Bad(Ser-155) was antagonized only by propranolol and was thus mediated through the beta-adrenoceptor. Inhibitor studies and partial purification of candidate kinases by fast protein liquid chromatography showed that the p90 ribosomal S6 kinases, p90RSK2/3 [which are activated by the extracellular signal-regulated kinases 1 and 2 (ERK1/2)] directly phosphorylated Bad(Ser-112), whereas the PKA catalytic subunit directly phosphorylated Bad(Ser-155). However, efficient phosphorylation of Bad(Ser-112) also required PKA activity. These data suggest that, although p90RSK2/3 phosphorylate Bad(Ser-112) directly, phosphorylation of this site is enhanced by phosphorylation of Bad(Ser-155). These phosphorylations potentially diminish the pro-apoptotic activity of Bad and contribute to the cytoprotective effects of phenylephrine and 8-(4-chlorophenylthio)-cAMP.

Mechanical, thermal and morphological characterization of polypropylene/biodegradable polyester blends with additives

The (bio)degradation of polyolefins can be accelerated by modifying the level of crystallinity or by incorporation of carbonyl groups by adding pro-oxidants to masterbatches or through exposure to ultraviolet irradiation. In this work we sought to improve the degradation of PP by adding cobalt, calcium or magnesium stearate to Ecoflex(R), PP or Ecoflex(R)/PP blends. The effect of the pro-oxidants on biodegradability was assessed by examining the mechanical properties and fluidity of the polymers. PP had higher values for tensile strength at break and Young`s modulus than Ecoflex(R), and the latter had little influence on the properties of PP in Ecoflex(R)/PP blends. However, the presence of pro-oxidants (except for calcium) reduced these properties. All of the pro-oxidants enhanced the fluidity of PP, a phenomenon that facilitated polymer degradation at high temperatures. (C) 2009 Elsevier Ltd. All rights reserved.

Efeito pró-inflamatório de uma lectina purificada da esponja marinha Cliona varians

A galactose and sucrose specific lectin from the marine sponge Cliona varians named CvL was purified by acetone fractionation followed by Sepharose CL 4B affinity chromatography. Models of leukocyte migration in vivo were used to study the inflammatory activity of CvL through of mouse paw oedema and peritonitis. Effect of CvL on peritoneal macrophage activation was analyzed. Effects of corticoids and NSAIDS drugs were also evaluated on peritonitis stimulated by CvL. Results showed that mouse hind-paw oedema induced by sub plantar injections of CvL was dependent dose until 50µg/paw. This CvL dose when administered into mouse peritoneal cavities induced maxima cell migration (9283 cells/µL) at 24 hours after injection. This effect was preferentially inhibited by incubation of CvL with the carbohydrates D-galactose followed by sucrose. Pre-treatment of mice with 3% thioglycolate increases the peritoneal macrophage population 2.3 times, and enhanced the neutrophil migration after 24h CvL injection (75.8%, p<0.001) and no significant effect was observed in presence of fMLP. Finally, Pre-treatment of mice with dexamethason (cytokine antagonist) decreased 65.6%, (p<0.001), with diclofenac (non-selective NSAID) decreased 34.5%, (p<0.001) and Celecoxib (selective NSAID) had no effect on leukocyte migration after submission at peritonitis stimulated by CvL, respectively. Summarizing, data suggest that CvL shows pro-inflammatory activity, inducing neutrophil migration probably by pathway on resident macrophage activation and on chemotaxis mediated by cytokines

The co-catalytic effect of chlorpromazine on peroxidase-mediated oxidation of melatonin: enhanced production of N-1-acetyl-N (2)-formyl-5-methoxykynuramine

Accumulating evidence points to relationships between increased production of reactive oxygen or decreased antioxidant protection in schizophrenic patients. Chlorpromazine (CPZ), which remains a benchmark treatment for people with schizophrenia, has been described as a pro-oxidant compound. Because the antioxidant compound melatonin exerts protective effects against CPZ-induced liver disease in rats, in this investigation, our main objective was to study the effect of CPZ as a co-catalyst of peroxidase-mediated oxidation of melatonin. We found that melatonin was an excellent reductor agent of preformed CPZ cation radical (CPZ(center dot+)). The addition of CPZ during the horseradish peroxidase (HRP)-catalyzed oxidation of melatonin provoked a significant increase in the rate of oxidation and production of N-1-acetyl-N-2-formyl-5-methoxykynuramine (AFMK). Similar results were obtained using myeloperoxidase. The effect of CPZ on melatonin oxidation was rather higher at alkaline pH. At pH 9.0, the efficiency of oxidation of melatonin was 15 times higher and the production of AFMK was 30 times higher as compared with the assays in the absence of CPZ. We suggest that CPZ is able to exacerbate the rate of oxidation of melatonin by an electron transfer mechanism where CPZ(center dot+), generated during the peroxidase-catalyzed oxidation, is able to efficiently oxidize melatonin.

Coenzyme Q(10) and its effects in the treatment of neurodegenerative diseases

According to clinical and pre-clinical studies, oxidative stress and its consequences may be the cause or, at least, a contributing factor, to a large number of neurodegenerative diseases. These diseases include common and debilitating disorders, characterized by progressive and irreversible loss of neurons in specific regions of the brain. The most common neurodegenerative diseases are Parkinson's disease, Huntington's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Coenzyme Q(10) (CoQ(10)) has been extensively studied since its discovery in 1957. It is a component of the electron transportation chain and participates in aerobic cellular respiration, generating energy in the form of adenosine triphosphate (ATP). The property of CoQ(10) to act as an antioxidant or a pro-oxidant, suggests that it also plays an important role in the modulation of redox cellular status under physiological and pathological conditions, also performing a role in the ageing process. In several animal models of neurodegenerative diseases, CoQ(10) has shown beneficial effects in reducing disease progression. However, further studies are needed to assess the outcome and effectiveness of CoQ(10) before exposing patients to unnecessary health risks at significant costs.

Tomate salada: uma alternativa como fonte de antioxidante para uso tópico

Tomato Salad: An Alternative as Antioxidant Source for Topic Use. Tomato is the principal source of lycopene, a carotenoid with high antioxidant activity which can be used topically as a phytocosmetic to combat skin aging. The aim of this study was to get a lycopene-rich extract from salad tomato pulp. The extract was analyzed using UV/vis spectroscopy, thin layer chromatography and high performance liquid chromatography. Oxidant activity was analyzed using the free radical DPPH method. The presence of lycopene in the salad tomato was confirmed. It was present in the apolar fraction rich in carotenoids, which was 96.70% lycopene. In the evaluation of the antioxidant activity, using the radical DPPH, the extract showed activity (IC(50) = 0,311 mg/mL). We conclude that the salad tomato can be used as a source of antioxidants for topic use.

Avaliação da estabilidade térmica e oxidativa do biodiesel de algodão e do efeito da adição de antioxidantes (α-tocoferol e BHT)

This work aims to study the effects of adding antioxidants, such as, α- tocopherol and BHT on the thermal and oxidative stability of biodiesel from cottonseed (B100). The Biodiesel was obtained through the methylical and ethylical routes. The main physical and chemical properties of cotton seed oil and the B100 were determined and characterized by FTIR and GC. The study of the efficiency of antioxidants, mentioned above, in concentrations of 200, 500, 1000, 1500, 2000ppm, to thermal and oxidative stability, was achieved by Thermogravimetry (TG), Differential Thermal Analysis (DTA), Differential Scanning Calorimetry (DSC), Differential Scanning Calorimetry - Hi-Pressure (P-DSC) and Rancimat. The Biodiesel obtained are within the specifications laid down by Resolution of ANP No7/2008. The results of TG curves show that the addition of both antioxidants, even in the lowest concentration, increases the thermal stability of Biodieseis. Through the DTA and DSC it was possible to study the physical and chemical transitions occurred in the process of volatilization and decomposition of the material under study. The initial time (OT) and temperature (Tp) of oxidation were determined through the P-DSC curve and they showed that the α-tocopherol has a pro-oxidant behavior for some high concentrations. The BHT showed better results than the α-tocopherol, with regard to the resistance to oxidation

Interaction of hypercaloric diet and physical exercise on lipid profile, oxidative stress and antioxidant defenses

The present study examined the interaction of hypercaloric diet (HD) and physical exercise on lipid profile and oxidative stress in serum and liver of rats. Male Wistar rats (60-days-old) were fed with a control (C) and hypercaloric diet (H). Each of the two dietary groups (C and H) was divided into three subgroups (n = 8), sedentary (CS and HS), exercised 2 days a week (CE2 and HE2) and exercised 5 days a week (CE5 and HE5). The swimming was selected as a model for exercise performance. After 8-weeks exercised rats showed decreased lactate dehydrogenase serum activities, demonstrating the effectiveness of the swimming as an aerobic-training protocol. Exercise 5-days a week reduced the body weight gain. Triacylglycerol (TG) and very low-density lipoprotein (VLDL-C) were increased in HD-fed rats. HE5 and CE5 rats had decreased TG, VLDL-C and cholesterol. HE2 rats had enhanced high-density lipoprotein (HDL-C) in serum. No alterations were observed in lipid hydroperoxide (LH), while total antioxidant substances (TAS) were increased in serum of exercised rats. HD-fed rats had hepatic TG accumulation. Superoxide dismutase activities were increased and catalase was decreased in liver of exercised rats. The interaction of HD and physical exercise reduced TAS and enhanced LH levels in hepatic tissue. In conclusion, this study confirmed the beneficial effect of physical exercise as a dyslipidemic-lowering component. Interaction of HD and physical exercise had discrepant effects on serum and liver oxidative stress. The interaction of HID and physical exercise reduced the oxidative stress in serum. HD and physical exercise interaction had pro-oxidant effect on hepatic tissue, suggesting that more studies should be done before using physical exercise as an adjunct therapy to reduce the adverse effects of HD. (c) 2006 Elsevier Ltd. All rights reserved.

Fullerene and omega-3 and omega-6 fatty acids on fish brain antioxidant status

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Conjugated linoleic acid and cardiac health: Oxidative stress and energetic metabolism in standard and sucrose-rich diets

Studies on conjugated linoleic acid ingestion and its effect on cardiac tissue are necessary for the safe utilization of this compound as supplement for weight loss. Male Wistar 24-rats were divided into four groups (n = 6):(C)given standard chow, water and 0.5 ml saline, twice a week by gavage; (C-CLA)receiving standard chow, water and 0.5 ml of conjugated linoleic acid, twice a week, by gavage; (S)given standard chow, saline by gavage, and 30% sucrose in its drinking water; (S-CLA)receiving standard chow, 30% sucrose in its drinking water and conjugated linoleic acid. After 42 days of treatment S rats had obesity with increased abdominal-circumference, dyslipidemia, oxidative stress and myocardial lower citrate synthase(CS) and higher lactate dehydrogenase(LDH) activities than C. Conjugated linoleic acid had no effects on morphometric parameters in C-CLA, as compared to C, but normalized morphometric parameters comparing S-CLA with S. There was a negative correlation between abdominal adiposity and resting metabolic rate. Conjugated linoleic acid effect, enhancing fasting-VO2/surface area, postprandial-carbohydrate oxidation and serum lipid hydroperoxide resembled to that of the S group. Conjugated linoleic acid induced cardiac oxidative stress in both fed conditions, and triacylglycerol accumulation in S-CLA rats. Conjugated linoleic acid depressed myocardial LDH comparing C-CLA with C, and beta-hydroxyacyl-coenzyme-A dehydrogenase/CS ratio, comparing S-CLA with S. In conclusion, dietary conjugated linoleic acid supplementation for weight loss can have long-term effects on cardiac health. Conjugated linoleic acid, isomers c9, t11 and t10, c12 presented undesirable pro-oxidant effect and induced metabolic changes in cardiac tissue. Nevertheless, despite its effect on abdominal adiposity in sucrose-rich diet condition, conjugated linoleic acid may be disadvantageous because it can lead to oxidative stress and dyslipidemic profile. (c) 2007 Elsevier B.V All rights reserved.

Oxidative stress in sickle cell disease: An overview of erythrocyte redox metabolism and current antioxidant therapeutic strategies

Erythrocytes have an environment of continuous pro-oxidant generation due to the presence of hemoglobin (Hb), which represents an additional and quantitatively significant source of superoxide (O2 •-) generation in biological systems. To counteract oxidative stress, erythrocytes have a self-sustaining antioxidant defense system. Thus, red blood cells uniquely function to protect Hb via a selective barrier allowing gaseous and other ligand transport as well as providing antioxidant protection not only to themselves but also to other tissues and organs in the body. Sickle hemoglobin molecules suffer repeated polymerization/depolymerization generating greater amounts of reactive oxygen species, which can lead to a cyclic cascade characterized by blood cell adhesion, hemolysis, vaso-occlusion, and ischemia-reperfusion injury. In other words, sickle cell disease is intimately linked to a pathophysiologic condition of multiple sources of pro-oxidant processes with consequent chronic and systemic oxidative stress. For this reason, newer therapeutic agents that can target oxidative stress may constitute a valuable means for preventing or delaying the development of organ complications. © © 2013 Elsevier Inc. All rights reserved.

Efeito dos exercícios aeróbio contínuo e com pesos combinados sobre a sinalização insulínica e transportador de glicose em musculatura esquelética de ratos obesos

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)