Inflamação e câncer: avaliação das vias CCL2 e TGFβ1 na carcinogênese prostática em ratos velhos submetidos à restrição proteica materna e ao consumo de açúcar até a idade adulta
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Data
2021-02-24
Autores
Fioretto, Matheus Naia
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
Estudos epidemiológicos e experimentais têm demonstrado maior índice de obesidade, diabetes e doenças cardiovasculares na população adulta de indivíduos cujas mães tiveram condições inadequadas durante a gravidez, como a restrição proteica materna (RPM). Recentemente, estudos experimentais demonstraram que o sistema reprodutivo da prole também é afetado pela RPM. Articulado a isso, o aumento do consumo de "açúcar de adição" no mundo tem sido associado ao aumento global de casos de doenças metabólicas. Englobado a esse contexto, a RPM e o consumo de açúcar podem estar associados a processos inflamatórios prostáticos com o envelhecimento. Portanto, este trabalho teve como objetivo investigar o papel das vias de inflamação em ratos submetidos à RPM e/ou consumo de açúcar, com foco na próstata ventral (PV). Foram utilizados ratos machos da prole Sprague Dawley submetidos ou não à RPM (CEUA 951). Após o desmame, ratos machos nascidos de mães alimentadas com dieta normoproteica (CTR, 17% de proteína) ou dieta hipoproteica (RPGL, 6% de proteína), durante a gestação e lactação, foram divididos em 4 grupos experimentais (n = 6 / grupo): Controle (CTR): Consumiu dieta normoproteica e água padrão atéo dia pós natal (DPN) ; Controle + açúcar (CTR + AÇU): Consumiu dieta normoproteica e solução açucarada (10% diluída em água) até DPN 90; Restrição Proteica Gestacional e Lactacional (RPGL): Recebeu água normal até DPN90; e RPGL + AÇU: Consumiram solução açucarada até DPN 90. No DPN 540 os animais foram anestesiados, pesados e eutanasiados. O sangue foi coletado e utilizado para análises sistêmicas e a PV para análises morfológicas e moleculares. Os resultados demonstram redução do peso corporal no grupo RPGL e RPGL + AÇU, aumento do peso relativo prostático, além de menor quantidade de gordura total. Os parâmetros metabólicos como glicose, triglicerídeos e proteínas totais não apresentaram diferenças significativas, assim como os parâmetros de estresse oxidativo, o que demonstra que as condições adversas não foram suficientes para desencadear processos como obesidade, diabetes e síndrome metabólica. Alterações teciduais na PV foram observadas em todos os grupos experimentais, com ênfase no infiltrado inflamatório e inflamação para os grupos RPGL e RPGL+AÇU. Em relação aos parâmetros inflamatórios, observou-se aumento de mastócitos e macrófagos CD68 na PV de todos os grupos experimentais, quando comparados ao CTR, além da incidência de carcinoma em alguns animais destes grupos. Verificamos alta expressão das moléculas de IL-6 no RPGL e aumento de TGF-b1 nos animais do grupo RPGL + AÇU, sistêmico e intra-prostático. Associado a isso, a SMAD2/3 fosforilada estava diminuída, o que pode demonstrar que essa via de inflamação é exacerbada no grupo que foi submetido às duas condições adversas. Com esses resultados, é possível observar influência da inflamação nos processos deletérios relacionados ao envelhecimento, tanto em animais submetidos à RPM, quanto ao consumo de açúcar, mas com maior ênfase naqueles que apresentavam ambas as condições adversas. Isso demonstra que a RPM e o consumo de açúcar afetam negativamente e diretamente a homeostase prostática na senilidade, com influência de parâmetros inflamatórios, podendo ter relação na biologia do câncer neste tecido.
Epidemiological and experimental studies have been demonstrated higher rate of obesity, diabetes and cardiovascular diseases in the adult population of individuals whose mothers had inadequate conditions during pregnancy, such as maternal low protein diet (LPD). Recently, experimental studies have demonstrated that the reproductive system are also affected by maternal LPD in the offspring rats. Linked to this, the increasing consumption of "added sugar" in the world has been associated to the global increase of metabolic diseases cases. Thus, maternal LPD and sugar consumption may be associated with inflammatory processes in the prostate with aging. Therefore, this project aims to investigate the role of inflammation pathways in rats submitted to maternal LPD, which together were exposed to sugar consumption, focusing on the ventral prostate (VP). Male Sprague Dawley offspring rats submitted or not to maternal LPD was used (CEUA951). Rats born from dams fed with control diet (CTR, 17% protein) or low protein diet (GLLP, 6% protein) during gestation and lactation period were divided in 4 experimental groups: Control (CTR) consumed control diet and water until PND 90; Control+sugar (CTR+SUG) consumed control diet and sugar solution (10% diluted in water) until PND 90; Gestational and Lactational Low Protein (GLLP) received normal water until PND 90; and GLLP+SUG consumed sugar solution until PND 90. On PDN 540 they were anesthetized, weighed, and euthanized. The collected blood was used for systemic analysis and the VP for morphological and molecular analysis. The results demonstrate a reduction in body weight in the GLLP and GLLP+SUG, an increase in the prostate relative weight, in addition to a lower amount of total fat. Metabolic parameters such as glucose, triglycerides and total proteins did not show significant differences, as well as oxidative stress parameters, which demonstrates that adverse conditions were not sufficient to trigger processes such as obesity, diabetes, and metabolic syndrome. Tissue changes in VP were observed in all experimental groups, with an emphasis on inflammatory infiltrate and inflammation for the GLLP and GLLP+SUG groups. Regarding inflammatory parameters, there was an increase in mast cells and CD68 macrophages in the VP of all groups when compared to CTR, in addition to the incidence of carcinoma in some animals in these groups. We observed a systemic and intra-prostate high expression of IL-6 molecules in the GLLP and an increase in TGF-b1 in the animals of the GLLP +SUG group. Associated with this, the phosphorylated SMAD2 3 was reduced, which can demonstrate that this inflammation pathway is exacerbated in the group that was submitted to both adverse conditions. With these results, it is possible to observe an influence of inflammation in the harmful processes related to aging, both in animals submitted to maternal LPD, and in the consumption of sugar, but with greater emphasis on those that presented both adverse conditions. This demonstrates that maternal LPD and sugar consumption negatively and directly affect prostatic homeostasis in senility, with the influence of inflammatory parameters, which may be related to the biology of cancer in this tissue.
Epidemiological and experimental studies have been demonstrated higher rate of obesity, diabetes and cardiovascular diseases in the adult population of individuals whose mothers had inadequate conditions during pregnancy, such as maternal low protein diet (LPD). Recently, experimental studies have demonstrated that the reproductive system are also affected by maternal LPD in the offspring rats. Linked to this, the increasing consumption of "added sugar" in the world has been associated to the global increase of metabolic diseases cases. Thus, maternal LPD and sugar consumption may be associated with inflammatory processes in the prostate with aging. Therefore, this project aims to investigate the role of inflammation pathways in rats submitted to maternal LPD, which together were exposed to sugar consumption, focusing on the ventral prostate (VP). Male Sprague Dawley offspring rats submitted or not to maternal LPD was used (CEUA951). Rats born from dams fed with control diet (CTR, 17% protein) or low protein diet (GLLP, 6% protein) during gestation and lactation period were divided in 4 experimental groups: Control (CTR) consumed control diet and water until PND 90; Control+sugar (CTR+SUG) consumed control diet and sugar solution (10% diluted in water) until PND 90; Gestational and Lactational Low Protein (GLLP) received normal water until PND 90; and GLLP+SUG consumed sugar solution until PND 90. On PDN 540 they were anesthetized, weighed, and euthanized. The collected blood was used for systemic analysis and the VP for morphological and molecular analysis. The results demonstrate a reduction in body weight in the GLLP and GLLP+SUG, an increase in the prostate relative weight, in addition to a lower amount of total fat. Metabolic parameters such as glucose, triglycerides and total proteins did not show significant differences, as well as oxidative stress parameters, which demonstrates that adverse conditions were not sufficient to trigger processes such as obesity, diabetes, and metabolic syndrome. Tissue changes in VP were observed in all experimental groups, with an emphasis on inflammatory infiltrate and inflammation for the GLLP and GLLP+SUG groups. Regarding inflammatory parameters, there was an increase in mast cells and CD68 macrophages in the VP of all groups when compared to CTR, in addition to the incidence of carcinoma in some animals in these groups. We observed a systemic and intra-prostate high expression of IL-6 molecules in the GLLP and an increase in TGF-b1 in the animals of the GLLP +SUG group. Associated with this, the phosphorylated SMAD2 3 was reduced, which can demonstrate that this inflammation pathway is exacerbated in the group that was submitted to both adverse conditions. With these results, it is possible to observe an influence of inflammation in the harmful processes related to aging, both in animals submitted to maternal LPD, and in the consumption of sugar, but with greater emphasis on those that presented both adverse conditions. This demonstrates that maternal LPD and sugar consumption negatively and directly affect prostatic homeostasis in senility, with the influence of inflammatory parameters, which may be related to the biology of cancer in this tissue.
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Palavras-chave
Restrição proteica materna, Açúcar, Próstata, Inflamação, Maternal protein restriction, Sugar, Ventral prostate, Inflammation