Leptina, ghrelina e exercício físico

A obesidade é atualmente um problema de saúde pública que provoca sérias conseqüências sociais, físicas e psicológicas. A etiologia da obesidade não é de fácil identificação, uma vez que a mesma é caracterizada como doença multifatorial de complexa interação entre fatores comportamentais, culturais, genéticos, fisiológicos e psicológicos. Recentes avanços na área de endocrinologia e metabolismo mostram que, diferentemente do que se acreditava há alguns anos, o adipócito sintetiza e libera diversas substâncias, não sendo apenas uma célula armazenadora de energia. Entre as substâncias liberadas pelo adipócito incluem-se a adiponectina, o fator de necrose tumoral-alfa, a interleucina-6 e a leptina. Especificamente, a leptina desempenha importante papel no controle da ingestão alimentar e no controle do peso corporal em mamíferos. Além disso, o hormônio ghrelina, recentemente descoberto, também parece influenciar o metabolismo energético e a obesidade. As alterações que o exercício físico provoca na fisiologia endócrino-metabólica podem contribuir sobremaneira para a prática clínica. Assim, essa revisão abordará os conhecimentos mais recentes sobre a leptina, a ghrelina e o papel dos diferentes tipos de exercício físico sobre estes hormônios. Os trabalhos mostram que a relação entre o exercício físico e a concentração plasmática desses peptídeos ainda não está clara. As razões para isso poderiam ser devidas aos diferentes protocolos de treinamento físico empregados nos estudos. Além disso, diferenças genéticas também podem explicar as discrepâncias entre os resultados obtidos em seres humanos, pois a existência de polimorfismo em alguns genes pode acarretar respostas celulares diferentes frente ao exercício físico.

Liver dysfunction in patients bitten by Crotalus durissus terrificus (Laurenti, 1768) snakes in Botucatu (State of São Paulo, Brazil)

Os autores estudaram 32 doentes picados por serpentes venenosas, sendo 16 picados por Bothrops spp. e 16 por Crotalus durissus terrificus. Trinta doentes eram do sexo masculino e dois do feminino com idades variando entre 8 e 63 anos (méda 33±15). A prova da retenção da bromosulfaleína apresentou-se aumentada na maioria dos doentes picados por serpentes Crotalus durissus terrificus. Houve correlação positiva entre a retenção da bromosulfaleína e os níveis séricos de alanina aminotransferase e entre alanina e aspartato aminotransferase apenas nos doentes do grupo Crotalus. Um dos doentes evoluiu para o óbito e apresentou no exame anatomopatológico do fígado degeneração hidrópica e lesões mitocondriais. Os autores concluem que as alterações hepáticas são causadas por pelo menos dois mecanismos a saber: lesão mitocondrial por efeito do veneno crotálico; efeito das citoquinas, especialmente a interleucina-6.

Annexin-A1 gene expression during liver development and post-translation modification after experimental endotoxemia

Objective and design: We have previously reported a role for annexin-A1 in liver proliferation and tumorogenicity as well as its action as an acute phase protein in a model of endotoxemia in interleukin-6 null mice.Material and methods: In this study, we have investigated the analysis of the gene and protein expression in annexin-A1 null mice and the wild type livers during foetal and adult life, and in the presence of a proinflammatory stimulus.Results: The data indicate a link between the expression of the annexin-A1 as serine-phosphorylated-protein during early events of the inflammatory response and as tyrosine-phosphorylated-form at later time-points, during the resolution of inflammation.Conclusions: The study of annexin-A1 post-translation modification may promote a new annexin-A1 peptide discovery programme to treat specific pathologies.

Plant derived alkaloid (-)-cassine induces anti-inflammatory and anti-hyperalgesics effects in both acute and chronic inflammatory and neuropathic pain models

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Antitumor effect of snake venoms

The search for biological antitumor agents has been pursued for over half a century. Snake venom has been shown to possess a wide spectrum of biological activities. The objectives of the present review are to evaluate the existing controversies on this subject published in a number of papers and to propose probable explanations for the phenomena observed. We reported our results obtained in a study, in which we evaluated the action of the venoms of Crotalus durissus terrificus and Bothrops jararaca on Ehrlich ascites tumor cells. We noticed an important antitumor effect, mainly with Bothrops jararaca venom, as well as an increase in the functional activity of macrophages. We also observed an increase in the number of mononuclear and polymorphonuclear cells with Bothrops jararaca venom. Considering these findings, we postulate that both Borhrops jararaca and Crotalus durissus terrificus venoms can act directly on tumor cells. In addition, we propose an indirect mechanism, based on the stimulation of the inflammatory response, to inhibit tumor growth and to promote its rejection.

Cytokine profile of Ehrlich ascites tumor treated with Bothrops jararaca venom

WE previously demonstrated that Bothrops jararaca venom (BjV) has an antitumor effect on Ehrlich ascites tumor (EAT) cells and induces an increase of polymorphonuclear leukocytes in early stages of tumor growth. It has been reported that this venom presents an important inflammatory effect when inoculated in animal models and in human snake-bites, and that cytokine levels have been detected in these cases. To evaluate whether the cytokines can be involved with the suppression of the tumoral growth, we evaluate the cytokine profile in the peritoneal cavity of mice inoculated with EAT cells and treated with BjV. Swiss mice were inoculated with EAT cells by the intraperitoneal route and treated with BjV venom (0.4 mg/kg, intraperitoneally), on the 1st, 4th, 7th, 10th, and 13th day. Mice were evaluated for cytokine levels on the 2nd, 5th, 8th, 11th and 14th day. Analysis was performed using an enzyme-linked immunosorbent assay for interleukin (IL)-1α, IL-2, IL-4, IL-6, IL-10, IL-13, and tumor necrosis factor-α (TNF-α) levels in the peritoneal washing supernatant. Results were analyzed statistically by the Kruskal-Wallis and Dunn's tests at the 5% level of significance. We observed that EAT implantation induces IL-6 production on the 11th and 14th days of tumor growth, IL-10 on the 11th day and TNF-α on the 14th day. The treatment with BjV suppresses production of these cytokines. In addition, IL-13 was produced by animals that were inoculated only with venom on the 11th and 14th days, and by the group inoculated with EAT cells and treated with venom on the 2nd and 14th days. Furthermore, we suggest that the IL-6 detected in the present study is produced by the EAT cells and the suppression of its production could be associated with the antitumor effect of BjV.

Cytokines and dietary energy restriction in stable chronic obstructive pulmonary disease patients

Tumour necrosis factor (TNF)-α has been found to be increased in malnourished chronic obstructive pulmonary disease (COPD) patients; however, the main cause of this phenomenon remains undetermined. In normal subjects, TNF-α production may be induced by dietary energy deprivation. The aim of this study was to investigate if stable COPD patients present alterations of inflammatory mediators after 48 h of dietary energy restriction. Fourteen COPD patients were admitted to the hospital while receiving an experimental diet with an energy content of approximately one-third of their energy needs. Clinical evaluation, nutritional assessment and serum levels of interleukin (IL)-6, TNF-α and C-reactive protein, and secretion of TNF-α by peripheral blood monocytes were assessed on admission and after the experimental diet. For reference values of the laboratory parameters, blood was collected from 10 healthy, elderly subjects. COPD patients showed significantly higher serum concentrations of IL-6 than control subjects, however, the experimental diet was not associated with statistically significant changes in the inflammatory mediators. The findings of this study, although preliminary because of the limited degree and duration of the energy restriction, suggest that the elevated levels of tumour necrosis factor-α, previously described in undernourished or weight-losing chronic obstructive pulmonary disease patients, may not be linked to a decrease of dietary energy intake.

Cyclosporin but not tacrolimus significantly increases salivary cytokine contents in rats

Background: Cyclosporin (CsA) and tacrolimus (FK-506) are immunosuppressive drugs that specifically inhibit T-cell activation via calcineurin inhibition. Gingival overgrowth is a common side effect following the administration of CsA. The severity of gingival overgrowth seen in patients taking FK-506 is less than that observed with CsA. Little is known about the involvement of saliva in drug-induced gingival overgrowth. The purpose of this study was to investigate the salivary contents of tumor growth factor β1 (TGF-β1), epidermal growth factor (EGF), and interleukin-6 (IL-6) as well as the hystometry of gingival tissue obtained from rats treated with either FK-506 or CsA. Methods: For 30 or 60 days rats received daily subcutaneous injection doses of either CsA or FK-506 (10 mg/kg). The concentrations of TGF-β1, EGF, and IL-6 in saliva were determined by enzyme-linked immunosorbent assay, and after histological processing, the oral epithelium and connective tissue were assessed at the region of the lower first molars. Results: The levels of TGF-β1, EGF, and IL-6 in saliva were not significantly altered by any of the treatments after 30 days. After 60 days of treatment with CsA, gingival overgrowth and significant increase in salivary TGF-β1, EGF, and IL-6 concentrations were observed; no statistically significant changes were induced by FK-506. Conclusion: Within the limits of this experimental study, it can be concluded that CsA, but not FK-506, induced gingival overgrowth associated with an increase of the salivary levels of the cytokines TGF-β1, EGF, and IL-6.

Role of natural killer cells in antitumor resistance

Natural killer cells constitute a population of lymphocytes able to non-specifically destroy virus-infected and some kinds of tumor cells. Since this lytic activity was shown by non-immunized animals the phenomenon is denominated natural killer (NK) activity and contrasts with specific cytotoxicity performed by cytolytic T lymphocytes (CTLs) because it does not depends on MHC-restricted peptides recognition. In fact, the main feature of most functional receptors of NK cells (NKRs) is their ability to be inhibited by different kinds of class I MHC antigens. In the middle of the 1950's, Burnet & Thomas forged the concept of tumor immunosurveillance and NK cells can be considered one of the main figures in this phenomenon both for effector and regulatory functions. In the present review the early studies on the biology of NK cells were revisited and both their antitumor activity and dependence on the activation by cytokines are discussed.

Cytokine and antibody production during murine leptospirosis

The aim of the present study was to investigate the kinetics of humoral and cellular responses during leptospirosis. We observed that the presence of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) was associated with antibody production and bacterial recovery, and the compromising of both TNF-α and IL-6 in the immunopathogenesis of leptospirosis during an experimental infection of BALB/c mice inoculated with Leptospira interrogans serovar Canicola was verified. Results showed higher levels of TNF-α and IL-6 in the initial phase of infection, in which the greatest bacterial clearance was observed. However, when the bacterial recovery was compared with the kinetics of the production of antibodies, the results revealed a kinetics proportionally inverted to antibody production. This fact may be related to some inhibitory factor which could be responsible for the selective suppression of the cellular immune response. We concluded that during leptospirosis there was a greater mobilization of the cellular immune response activity, mainly in the initial phase of the infectious process, for posterior involvement of the humoral response, and that both TNF-α and IL-6 could be associated with the immunopathogenesis of the disease.

Pro- and anti-inflammatory cytokines produced by human monocytes challenged in vitro with Paracoccidioides brasiliensis

Monocytes and macrophages play a central role in innate and adaptive immune response against systemic fungal infections. Imbalances in suppressor or stimulatory cytokine secretion caused by these cells may influence disease development, microorganism death, and the nature of the adaptive immune response. This study analyzed the monocyte cytokine profiles of healthy individuals challenged with high and low virulent strains of P. brasiliensis and mRNA cytokine expression kinetics by reverse transcription polymerase chain reaction (RT-PCR). Peripheral blood monocytes from healthy volunteers were cultured in vitro with and without virulent (Pb18) or low virulence (Pb265) strains from P. brasiliensis viable yeast cells. Interleukin-1 beta (IL-1β), IL-6, IL-8, IL-10, tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-β1) were measured in culture supernatants by enzyme immunoassay (ELISA), and mRNA cytokine expression was determined by RT-PCR at 0, 4, 8, 12, 18 and 48 hr. Both P. brasiliensis strains induced monocyte production of IL-1β, IL-6, IL-10 and TNF-α. Pb18 induced higher levels of IL-1β, IL-6, and IL-10 than Pb265. IL-8 and TGF-β1 levels were not significantly different from those cultured without stimulus. The mRNA cytokine expression was similar to supernatant cytokines measured by ELISA. In vitro monocyte challenge with virulent P. brasiliensis strain induces earlier and higher levels of pro- and anti-inflammatory cytokines than low virulence strain.

Cytokine gene variants and venous thrombotic risk in the BRATROS (BRAZILIAN THROMBOSIS STUDY)

Introduction: Venous thrombosis (VT) and inflammation are two closely related entities. In the present investigation we assessed whether there is a relation between genetic modifiers of the inflammatory response and the risk of VT. Materials and methods: 420 consecutive and unrelated patients with an objective diagnosis of deep VT and 420 matched controls were investigated. The frequencies of the following gene polymorphisms were determined in all subjects: TNF-α- 308 G/A, LT-α+ 252 A/G, IL-6-174 G/C, IL1-ra 86 bp VNTR, IL-10-1082 A/G and CD-31 125 C/G. Results: Overall odds ratio (OR) for VT related to TNF-α- 308 G/A, LT-α+ 252 A/G, IL-6-174 G/C, A1 allele (4 bp repeat) of the IL1-ra 86 bp VNTR, IL-10-1082 A/G and CD-31 125 C/G were respectively: 1.0 (CI95: 0.8-1.5), 1.3 (CI95: 1.0-1.7), 1.1 (CI95: 0.9-1.5), 1.6 (CI95: 1-2.5), 1.2 (CI95: 0.8-1.7) and 0.8 (CI95: 0.6-1.1). A possible interaction between polymorphisms was observed only for the co-inheritance of the mutant alleles of the LT-α+ 252 A/G and IL-10-1082 G/A polymorphisms (OR = 2; CI95: 1.1-3.8). The risk of VT conferred by factor V Leiden and FII G20210A was not substantially altered by co-inheritance with any of the cytokine gene polymorphisms. Conclusions: Cytokine gene polymorphisms here investigated did not significantly influence venous thrombotic risk. © 2006 Elsevier Ltd. All rights reserved.

Infantile epileptic encephalopathy with hypsarrhythmia (infantile spasms/west syndrome) and immunity

West syndrome is a severe epilepsy, occurring in infancy, that comprises epileptic seizures known as spasms, in clusters, and a unique EEG pattern, hypsarrhythmia, with psychomotor regression. Maturation of the brain is a crucial component. The onset is within the first year of life, before 12 months of age. Patients are classified as cryptogenic (10 to 20%), when there are no known or diagnosed previous cerebral insults, and symptomatic (80 to 90%), when associated with pre-existing cerebral damages. The time interval from a brain insult to infantile spasms onset ranged from 6 weeks to 11 months. West syndrome has a time-limited natural evolutive course, usually disappearing by 3 or 4 years of age. In 62% of patients, there are transitions to another age-related epileptic encephalopathies, the Lennox-Gastaut Syndrome and severe epilepsy with multiple independent foci. Spontaneous remission and remission after viral infections may occur. Therapy with ACTH and corticosteroids are the most effective. Reports about intravenous immunoglobulins action deserve attention. There is also immune dysfunction, characterized mainly by anergy, impaired cell-mediated immunity, presence of immature thymocytes in peripheral blood, functional impairment of T lymphocytes induced by plasma inhibitory factors, and altered levels of immunoglobulins. Changes in B lymphocytes frequencies and increased levels of activated B cells have been reported. Sensitized lymphocytes to brain extract were also described. Infectious diseases are frequent and may, sometimes, cause fatal outcomes. Increase of pro-inflamatory cytokines in serum and cerebrospinal fluid of epileptic patients were reported. Association with specific HLA antigens was described by several authors (HLA-DR7, HLA-A7, HLA-DRw52, and HLA-DR5). Auto-antibodies to brain antigens, of several natures (N-methyl-d-aspartate glutamate receptor, gangliosides, brain tissue extract, synaptic membrane, and others), were described in epileptic patients and in epileptic syndromes. Experimental epilepsy studies with anti-brain antibodies demonstrated that epileptiform discharges can be obtained, producing hyperexcitability leading to epilepsy. We speculate that in genetically prone individuals, previous cerebral lesions may sensitize immune system and trigger an autoimmune disease. Antibody to brain antigens may be responsible for impairment of T cell function, due to plasma inhibitory effect and also cause epilepsy in immature brains. © 2008 Bentham Science Publishers Ltd.

Utilization of neuromuscular electrical stimulation in the acute phase of ankle immobilization at 90°: Study in rats

Objective: To evaluate the skeletal muscle glycogen content and plasmatic concentration of interleukin -6 (IL-6), interleukin-4 (IL-4), interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNF-α) in rats submitted to electrical stimulation sessions during the first three days of ankle immobilization at the position of 90°. Methods: Albinomale Wistar rats(3-4 months) were maintained in vivarium. conditions with food and water ad libitum, Submitted to 12 h photoperiodic cycles of light/dark, and distributed into 7 experimental groups (n = 6): control(C), immobilized 1 day(I1) immobilized 1 day and electrically stimulated(IE1) immobilized 2 days(12), immobilized 2 days and electrically stimulated(IE2), immobilized 3 days(13) and immobilized 3 days and electrically stimulated(IE3). Groups I utilized an acrylic resin orthesis model and groups electrically stimulated (IE) utilized the orthesis and a session of electrotherapy by a Dualpex 961 (biphasic quadratic pulse, 10 Hz, 0.4 ms, 5.0 mA, one 20 min session a day). After the experimental period, the rats were anesthetized with pentobarbital sodium(40 mg/kg) and a blood sample was colleted to evaluate the plasmatic concentration of interleukins by means of the radioimmunoassay method. The soleus and the white portion of the gastrocnemius muscle were colleted for glycogen reserves analysis(GLY). Other groups of rats were used to apply the glucose tolerance test(GTT) and insulin tolerance test(ITT). For statistical analysis, the Kolmogorov-Smirnov normality test followed by ANOVA and the Tukey tests were utilized, with a critical level established at 5%. Results: In ITT test, groups IE enhanced the skeletal muscle glucose uptake, but no changes were observed in GTT after the therapy session, which indicates that electrical stimulation is a sensibilizing method to augment skeletal muscle glucose uptake. The GLY reserves were reduced in I groups, which indicate that disuse altered insulin sensitivity and compromised energetic homeostasis. However. the IE groups displayed an augment in GLY content, suggesting that electrical stimulation restores the enzymatic pathways altered by immobilization. The improvement in GLY was accompanied by an elevation of the plasmatic concentration of IL-6 and TNF-α, showing the participation of these interleukins in the control of metabolic profile. Plasmatic concentrations of IL-10 were elevated only after 3 days of IE while IL-4 did not display any modifications. Conclusion: The results suggest that neuromuscular electricaf stimulation is an important toot in the maintenance of energetic, conditions of musculature submitted to immobilization, and presents multifactor mechanisms linked to interleukins action that converge to maintain the energetic equilibrium of the tissue in disuse.

Cardiac remodeling induced by smoking: Concepts, relevance, and potential mechanisms

Cardiac or ventricular remodeling is characterized by molecular, cellular, and interstitial alterations that lead to changes in heart size, mass, geometry and function in response to a given insult. Currently, tobacco smoke exposure is recognized as one of these insults. Indeed, tobacco smoke exposure induces the enlargement of the left-sided cardiac chambers, myocardial hypertrophy, and ventricular dysfunction. Potential mechanisms for these alterations include hemodynamic and neurohormonal changes, oxidative stress, inflammation, nitric oxide bioavailability, matrix metalloproteinases and mitogen-activated protein kinase activation. This review will focus on the concepts, relevance, and potential mechanisms of cardiac remodeling induced by tobacco smoke. © 2012 Bentham Science Publishers.