Adipocytes and macrophages interplay in the orchestration of tumor microenvironment : new implications in cancer progression

Inflammation has been known as one of the main keys to the establishment and progression of cancers. Chronic low-grade inflammation is also a strategic condition that underlies the causes and development of metabolic syndrome and obesity. Moreover, obesity has been largely related to poor prognosis of tumors by modulating tumor microenvironment with secretion of several inflammatory mediators by tumor-associated adipocytes (TAAs), which can modulate and recruit tumor-associated macrophages. Thus, the understanding of cellular and molecular mechanisms that underlay and link inflammation, obesity, and cancer is crucial to identify potential targets that interfere with this important route. Knowledge about the exact role of each component of the tumor microenvironment is not yet fully understood, but the new insights in literature highlight the essential role of adipocytes and macrophages interplay as key factor to determine the fate of cancer progression. In this review article, we focus on the functions of adipocytes and macrophages orchestrating cellular and molecular mechanisms that lead to inflammatory modulation in tumor microenvironment, which will be crucial to cancer establishment. We also emphasized the mechanisms by which the tumor promotes itself by recruiting and polarizing macrophages, discussing the role of adipocytes in this process. In addition, we discuss here the newest possible anticancer therapeutic treatments aiming to retard the development of the tumor based on what is known about cancer, adipocyte, and macrophage polarization

Adipocytes and Macrophages Interplay in the Orchestration of Tumor Microenvironment: New Implications in Cancer Progression

Inflammation has been known as one of the main keys to the establishment and progression of cancers. Chronic low-grade inflammation is also a strategic condition that underlies the causes and development of metabolic syndrome and obesity. Moreover, obesity has been largely related to poor prognosis of tumors by modulating tumor microenvironment with secretion of several inflammatory mediators by tumor-associated adipocytes (TAAs), which can modulate and recruit tumor-associated macrophages. Thus, the understanding of cellular and molecular mechanisms that underlay and link inflammation, obesity, and cancer is crucial to identify potential targets that interfere with this important route. Knowledge about the exact role of each component of the tumor microenvironment is not yet fully understood, but the new insights in literature highlight the essential role of adipocytes and macrophages interplay as key factor to determine the fate of cancer progression. In this review article, we focus on the functions of adipocytes and macrophages orchestrating cellular and molecular mechanisms that lead to inflammatory modulation in tumor microenvironment, which will be crucial to cancer establishment. We also emphasized the mechanisms by which the tumor promotes itself by recruiting and polarizing macrophages, discussing the role of adipocytes in this process. In addition, we discuss here the newest possible anticancer therapeutic treatments aiming to retard the development of the tumor based on what is known about cancer, adipocyte, and macrophage polarization

Revealing a novel Otubain-Like Enzyme from Leishmania infantum with deubiquitinating activity toward K48-linked substrate

Deubiquitinating enzymes (DUBs) play an important role in regulating a variety of eukaryotic processes. In this context, exploring the role of deubiquitination in Leishmania infantum could be a promising alternative to search new therapeutic targets for leishmaniasis. Here we present the first characterization of a DUB from L. infantum, otubain (OtuLi), and its localization within parasite. The recombinant OtuLi (rOtuLi) showed improved activity on lysine 48 (K48)-linked over K63-linked tetra-ubiquitin (Ub) and site-directed mutations on amino acids close to the catalytic site (F82) or involved in Ub interaction (L265 and F182) caused structural changes as shown by molecular dynamics, resulting in a reduction or loss of enzyme activity, respectively. Furthermore, rOtuLi stimulates lipid droplet biogenesis (an inflammatory marker) and induces IL-6 and TNF-a secretion in peritoneal macrophages, both proinflammatory cytokines. Our findings suggest that OtuLi is a cytoplasmic enzyme with K48-linked substrate specificity that could play a part in proinflammatory response in stimulated murine macrophages

Efeito do suco de laranja sobre biomarcadores relacionados ao excesso de peso e ao câncer

O objetivo desta pesquisa foi verificar o efeito do suco de laranja (SL) sobre dois tipos de condições, cuja as etiologias podem estar intimamente associadas a uma alimentação desequilibrada: o excesso de peso e o câncer. Baseado nessa abordagem, nós escolhemos avaliar os efeitos do SL em dois modelos experimentais diferentes: em humanos com excesso de peso (in vivo) e em cultura de células leucêmicas (in vitro). No experimento in vivo foram avaliados os níveis séricos de biomarcadores metabólicos, inflamatórios e oxidativos de indivíduos com peso normal e com sobrepeso após o consumo de oito semanas de suco de laranja blond (SLB). Os indivíduos foram divididos de acordo com o índice de massa corporal (IMC) em dois grupos: Peso normal e Sobrepeso. Em ambos os grupos, os indivíduos ingeriram 750 mL de SL diariamente. Foram avaliados a composição corporal (peso, estatura, IMC, gordura e circunferência da cintura), biomarcadores metabólicos (colesterol total, LDL-C, HDL-C, triglicérides, glicose, insulina, resistência à insulina e hemoglobina glicada), inflamatórios (proteína C reativa, IL-4, IL-10, IL-12, TNF-? e IFN-?) e oxidativos (malondialdeído e DPPH??). Os resultados mostraram que após o consumo de SLB, as medidas da composição corporal não foram alteradas em nenhum dos grupos. Entretanto, houve redução nos níveis de lipídeos séricos, aumento da citocina IL-12, diminuição da proteína C reativa e aumento na capacidade antioxidante em indivíduos com peso normal e sobrepeso. No experimento in vitro foram examinados o crescimento, o ciclo e apoptose celular após a administração do suco de laranja blond (SLB), do suco de laranja vermelha (SLV) e da hesperidina (HSP) em uma nova linhagem celular de leucemia linfoblástica aguda de células T (Loucy). A distribuição do ciclo celular e a morte celular por apoptose foram determinadas utilizando citometria de fluxo. A secreção das citocinas ...The objective of this study was to verify the effect of orange juice (OJ) on two types of conditions whose etiologies may be closely associated with an unbalanced diet: overweight and cancer. Based on this approach, we chose to evaluate the effects of OJ in two different experimental models: in overweight humans (in vivo) and in cultured leukemic cells (in vitro). In the in vivo experiment were evaluated serum levels of metabolic, inflammatory and oxidative biomarkers of normal weight and overweight after consuming eight weeks of blond orange juice (BOJ). The subjects were divided according to body mass index (BMI) in two groups: normal weight and overweight. In both groups, subjects ingested 750 ml of BOJ daily. Body composition (weight, height, BMI, fat and waist circumference), metabolic biomarkers (total cholesterol, LDL-C, HDL-C, triglycerides, glucose, insulin, insulin resistance and glycated hemoglobin), inflammatory (protein were evaluated C reactive protein, IL-4, IL-10, IL-12, TNF-? and IFN-?) and oxidation (malondialdehyde and DPPH??). The results showed that after BOJ consumption, the measurements of body composition were not altered in either group. However, there was a reduction in serum lipid levels, increased cytokine IL-12, decreased C-reactive protein and increased of antioxidant capacity in normal and overweight. In the in vitro study, the growth, cycle and apoptosis cell were examined after administration of BOJ juice, red orange juice (ROJ), and hesperidin (HSP) into a new acute lymphoblastic leukemia cell line T cells (Loucy). The cell cycle distribution and apoptotic cell death were determined using flow cytometry. The secretion of IL-1?, IL1-?, IL-2, IL-4, IL-6, IL-10, IL-17A, IFN?, TNF?, TGF?, and MIP? were evaluated by ELISA array. BOJ and ROJ caused no alterations in cell proliferation, but both reduced cell viability by about 25%. BOJ induced cell cycle arrest in G0/G1 phase and decreased the ...Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Efeito do suco de laranja e da glicosil hesperidina sobre o sistema imune inato de camundongos

Tem sido mostrado que a hesperidina, um flavonóide encontrado nas frutas cítricas e especialmente no suco de laranja, apresenta atividade antiinflamatória e imunomodulatória, entre outras. O presente estudo avaliou os efeitos da ingestão do suco de laranja (SL) como fonte natural da hesperidina, da glicosil hesperidina isolada (GH) e da mistura de ambos (SL-GH), sobre o sistema imune inato de camundongos. Para tanto, foram medidos os parâmetros de produção e inibição da produção de óxido nítrico (NO), e de liberação das citocinas IL-10, IL-12 e TNF- em culturas de macrófagos peritoneais ex vivo. Os macrófagos foram obtidos de grupos de animais previamente tratados com GH, SL, SL-GH ou solução salina (SS). Em seguida as células foram tratadas com GH e lipopolissacarídeo bacteriano (LPS) in vitro. Os resultados mostraram que o tratamento com suco de laranja estimulou a produção de NO de forma moderada (60μmol de NO- 2) pelos macrófagos, aumentou a liberação da citocina IL-10 e diminuiu significativamente a produção de TNF- . O tratamento com G-hesperidina inibiu completamente a produção de NO em macrófagos mesmo na presença de LPS, aumentou a produção da citocina IL-12 e diminuiu a produção de IL-10. Estes resultados sugerem que a ingestão de suco de laranja é benéfica ao sistema imune, podendo apresentar ação contra possíveis agentes infecciosos. A flavanona Ghesperidina isolada pode ser considerada um composto anti-inflamatório nos casos onde ocorre a intensa liberação de óxido nítrico, tais como as doenças inflamatóriasIt has been shown that hesperidin, a flavonoid found in citrus fruits and especially in the orange juice, has anti-inflammatory and immunomodulatory, among others. This study evaluated the effects of ingestion of orange juice (SL) as a natural source of hesperidin, isolated glucosyl hesperidin (GH) and a mixture of both (SL-GH) on the innate immune system of mice. To this end, it was measured the parameters of production and inhibiting the production of nitric oxide (NO), and release of cytokines IL-10, IL-12 and TNF-α in cultures of peritoneal macrophages ex vivo. Macrophages were obtained from groups of animals previously treated with GH, SL, SL-GH or saline solution. Then the cells were treated with GH and bacterial lipopolysaccharide (LPS) in vitro. The results showed that treatment with orange juice stimulated the production of NO in a moderate (60µmol NO- 2) by macrophages, increased the release of cytokine IL-10 and significantly decreased the production of TNF-α. Treatment with G-hesperidin completely inhibited NO production in macrophages, even in the presence of LPS, increased the production of cytokine IL-12 and decreased production of IL-10. These results suggest that ingestion of orange juice is beneficial to the immune system, may bring suit against possible infectious agents. The isolated G-flavanone hesperidin can be considered an anti- inflammatory compound in cases where it occurs intense release of nitric oxide, such as inflammatory diseasesConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Hesperidin associated with continuous and interval swimming improved biochemical and oxidative biomarkers in rats

Background: Citrus flavonoids, such as hesperidin, have shown therapeutic properties that improve hyperglycemia and insulin resistance, and decrease blood serum lipids and inflammation. The current investigation studied the effects of hesperidin supplementation associated with continuous and interval swimming on the biochemical parameters (glucose, cholesterol and triglycerides), and oxidative stress markers (TBARS and DPPH) in rats.Methods: The animals (n = 60) were randomly divided in six groups: negative (C) and positive control (CH) for hesperidin supplementation, and continuous or interval swimming without (CS and IS) or with hesperidin supplementation (CSH and ISH). Hesperidin was given by gavage for four weeks (100 mg/kg body mass) before the exercise. Continuous swimming was performed for 50 min with loads from 5% to 8 % of body weight from the first to fourth week, while interval swimming training was performed for 50 min in sessions of 1 min of swimming followed by 2 min of resting, carrying loads from 10% to 15, 20 and 25% from the first to fourth week. At the end of the experiment, blood serum samples were draw to perform analysis of glucose, total cholesterol, HDL-C and triglycerides. Oxidative biomarkers were evaluated by lipid peroxidation (TBARS) and antioxidant capacity assay (DPPH) of the blood serum.Results: There was a continuous decline of serum glucose from C (100%) > CH (97%) > CS (94%) > CSH (91%, p < .05), IS (87%, p < .05) > ISH (80%, p < .05), showing a combined beneficial effect of hesperidin and swimming. Also, continuous or intermittent swimming with hesperidin supplementation lowered total cholesterol (-16%, p < .05), LDL-C (-50%, p < 0.05) and triglycerides (-19%, p < 0.05), and increased HDL-C (48%, p < .05). Furthermore, hesperidin enhanced the antioxidant capacity on the continuous swimming group (183%, p < .05) and lowered the lipid peroxidation on the interval swimming group (-45%, p < .05).Conclusions: Hesperidin supplementation per se, or in combination with swimming exercise protocols, improved the biochemical profile and antioxidant biomarkers evidencing that the use of flavanones may enhance the health benefits promoted by exercise. © 2013 de Oliveira et al.; licensee BioMed Central Ltd

Avaliação do estresse oxidativo no sangue de consumidores habituais de suco de laranja

Two biomarkers of oxidative stress were evaluated in healthy volunteers treated with daily doses of orange juice that is well known source of vitamin C and citric flavanones, which have been associated with antioxidant, anti-inflammatory and hypolipidemic effects. The antioxidant capacity in the blood serum was evaluated by studying the scavenging of 2,2'-diphenyl-1-picrylhydrazyl (DPPH) free radical, and also lipid peroxidation was evaluated by the thiobarbituric acid reacting substances (TBARS) assay. The results have shown that the regular consumption of orange juice increased 150% and 200% the serum antioxidant capacity for women and men respectively, but it was no significant change in the serum lipid peroxidation. In conclusion, the increase of flavonones and vitamin C in the body due to the regular intake of orange juice expressively improved the antioxidant capacity, but without significant effect on the lipid peroxidation.Dois biomarcadores do estresse oxidativo foram avaliados em indivíduos saudáveis que receberam doses diárias de suco de laranja, notadamente uma fonte de vitamina C e de flavanonas, que têm sido associadas aos efeitos antioxidante, anti-inflamatório e hipolipidêmico. A capacidade antioxidante do soro sanguíneo foi avaliada através da redução do radical 2,2-difenil-1-picril-hidrazila (DPPH) e a peroxidação lipídica foi avaliada pela presença de substâncias reativas ao ácido tiobarbitúrico (TBARS). Os resultados mostraram que após o período de suplementação com o suco de laranja houve um aumento 150% na capacidade antioxidante no soro das mulheres e 200% no soro dos homens (p<0,001), mas não houve alteração na peroxidação lipídica no sangue dos voluntários. Concluindo, o aumento das reservas de flavanonas e de vitamina C, decorrente da ingestão regular de suco de laranja, melhorou expressivamente a capacidade antioxidante no sangue, sem, entretanto, apresentar efeito sobre a peroxidação lipídica

Orange Juice and Hesperidin Promote Differential Innate Immune Response in Macrophages ex vivo

The purpose of this study was to verify the immune response induced by intake of orange juice or hesperidin on macrophages through the secretion of cytokines and nitric oxide. Mice were divided in three groups treated orally with orange juice, hesperidin, or control for 2 weeks. Ex vivo macrophages from all groups of mice were cultured with or without lipopolysaccharide (LPS)-stimuli, and the levels of nitric oxide (NO) and of the cytokines IL-10, IL-12, and TNF-alpha were evaluated. Macrophages of non-LPS-stimulated, orange juice treatment increased IL-12 levels by 143 % and the other cytokines and NO levels were unchanged. Hesperidin treatment increased IL-12 levels by 72 % and strongly decreased the NO secretion. For LPS-stimulated macrophages the orange juice (OJ) treatment decreased TNF-alpha secretion by 100 % and did not alter other cytokines, while NO levels increased 41 %. Hesperidin treatment decreased NO, IL-10, IL-12, and TNF-alpha levels by 56 %, 47 %, 29 %, and 63 %, respectively. In conclusion, OJ and hesperidin showed different immune responses, suggesting that hesperidin displays a suppressive effect on inflammation generated by LPS, while OJ seems to enhance the functions of macrophages associated with antimicrobial activity.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Efeito da suplementação com ácido linoléico conjugado e do treinamento em natação sobre a composição corporal e os parâmetros bioquímicos de ratos Wistar em crescimento Effect of conjugated linoleic acid supplementation and swimming training on the body composition and biochemical parameters of Wistar pups

OBJETIVO: Avaliar os efeitos da suplementação com ácido linoléico conjugado, associada ao treinamento moderado em natação, sobre a composição corporal, o consumo e a eficiência alimentar, a glicemia, o perfil lipídico e o glicogênio muscular e hepático de ratos Wistar. MÉTODOS: Ratos Wistar (30 dias) foram divididos em: sedentário, sedentário suplementado, treinado e treinado suplementado. Permaneceram em gaiolas individuais com comida e água ad libitum, temperatura de 23ºC (com variação de1ºC) e ciclo claro-escuro de 12 horas, durante 8 semanas. A sessão de natação durou 1 hora e foi realizada três vezes/semana, bem como a suplementação com ácido linoléico conjugado a 2%. Após sacrifício, o plasma, os tecidos adiposos brancos e o marrom, o músculo gastrocnêmio e o fígado foram coletados e pesados. RESULTADOS: A suplementação per se não promoveu modificação na ingestão alimentar e na massa corporal dos animais. Houve aumento na glicemia de jejum (p<0,05), nas lipoproteínas de alta densidade (p<0,05), no colesterol total (p<0,05) e redução dos triacilgliceróis. A suplementação associada ao treinamento reduziu a massa corporal (p<0,05) e aumentou o peso relativo do tecido adiposo, do fígado e a glicemia de jejum. CONCLUSÃO: A suplementação com ácido linoléico conjugado associada à prática de exercício físico parece ter influência no balanço energético, mas, por outro lado, o aumento no peso do fígado indica que a ingestão deste ácido graxo pode ter efeitos indesejáveis, aumentando as chances de desenvolvimento do fígado gorduroso. Estes achados apontam perspectivas para novos estudos envolvendo análises histológicas do fígado, expressão gênica de enzimas chaves do metabolismo lipídico e de carboidratos, associados ou não a diferentes protocolos de treinamento físico.<br>OBJECTIVE: The objective of this study was to evaluate the effects of conjugated linoleic acid supplementation associated with moderate swimming training on body composition, food efficiency and consumption, blood glucose, lipid profile, and muscle and liver glycogen of Wistar rats. METHODS: Thirty-day old Wistar rats were divided into the following groups: inactive, inactive with 2% conjugated linoleic acid supplementation, active, and active with 2% conjugated linoleic acid supplementation. They remained in individual cages with food and water ad libitum, temperature of 23±1ºC and a light and dark cycle of 12 hours for 8 weeks. The active groups swam for one hour three times per week. The animals were killed and the plasma, white and brown fat tissues, gastrocnemius muscle and liver were collected and weighted. RESULTS: Supplementation per se did not promote food intake or body weight changes in the animals. Fasting glucose (p<0.05) and high density lipoproteins (HDL, p<0.05) increased and triacylglycerols decreased. Supplementation associated with activity decreased body mass (p<0.05) and increased the relative weight of fat tissues, liver and fasting glucose. CONCLUSION: Conjugated linoleic acid supplementation associated with physical activity seems to influence energy balance. On the other hand, the increased liver weight indicates that intake of this fatty acid may have undesirable side-effects, increasing the chances of developing fatty liver. This new perspective makes way for new studies including histological analyses of the liver and gene expression of key enzymes from the lipid and carbohydrate metabolism, associated or not with different physical training protocols

A transformação da educação em mercadoria no Brasil The transformation of education into commodity in Brazil

O presente artigo apresenta pesquisa que estuda as consequências perceptíveis do processo de penetração dos fundos financeiros na educação superior no Brasil e, posteriormente, a emissão de ações de instituições de ensino diretamente na bolsa de valores. Entre os resultados observados encontra-se o rápido crescimento das instituições que adotaram tal estratégia. A forma mais visível desse crescimento é a compra de outras instituições e seu aperfeiçoamento, por meio da implantação de uma gestão mais profissionalizada. Tal processo tem propiciado o crescimento acelerado de algumas instituições, generalizando a educação como uma mercadoria, assim como a tendencial oligopolização da oferta. Conclui-se afirmando que é cabível falar-se em uma financeirização da educação, posto que é o setor financeiro que assume a hegemonia na educação privada no país.<br>This paper presents a research on the noticeable consequences of the supply of private equities and venture capital in Brazilian Higher Education and of the subsequent going public of many teaching institutions. These are growing fast, mainly through the purchase of other schools, whose administration is professionalized. Such process has generalized both education as a commodity and the oligopolization of provision. It is thus possible to conclude that education has been financialized, since private education is nowadays hegemonic in Brazil