ABSTRACT
Drug-associated reward memories are conducive to intense craving and often trigger relapse. Simvastatin has been shown to regulate lipids that are involved in memory formation but its influence on other cognitive processes is elusive. Here, we used a mass spectrometry-based lipidomic method to evaluate the impact of simvastatin on the mouse brain in a cocaine-induced reinstatement paradigm. We found that simvastatin blocked the reinstatement of cocaine-induced conditioned place preference (CPP) without affecting CPP acquisition. Specifically, only simvastatin administered during extinction prevented cocaine-primed reinstatement. Global lipidome analysis showed that the nucleus accumbens was the region with the greatest degree of change caused by simvastatin. The metabolism of fatty-acids, phospholipids, and triacylglycerol was profoundly affected. Simvastatin reversed most of the effects on phospholipids induced by cocaine. The correlation matrix showed that cocaine and simvastatin significantly reshaped the lipid metabolic pathways in specific brain regions. Furthermore, simvastatin almost reversed all changes in the fatty acyl profile and unsaturation caused by cocaine. In summary, pre-extinction treatment with simvastatin facilitates cocaine extinction and prevents cocaine relapse with brain lipidome remodeling.
ABSTRACT
Drug-associated reward memories are conducive to intense craving and often trigger relapse. Simvastatin has been shown to regulate lipids that are involved in memory formation but its influence on other cognitive processes is elusive. Here, we used a mass spectrometry-based lipidomic method to evaluate the impact of simvastatin on the mouse brain in a cocaine-induced reinstatement paradigm. We found that simvastatin blocked the reinstatement of cocaine-induced conditioned place preference (CPP) without affecting CPP acquisition. Specifically, only simvastatin administered during extinction prevented cocaine-primed reinstatement. Global lipidome analysis showed that the nucleus accumbens was the region with the greatest degree of change caused by simvastatin. The metabolism of fatty-acids, phospholipids, and triacylglycerol was profoundly affected. Simvastatin reversed most of the effects on phospholipids induced by cocaine. The correlation matrix showed that cocaine and simvastatin significantly reshaped the lipid metabolic pathways in specific brain regions. Furthermore, simvastatin almost reversed all changes in the fatty acyl profile and unsaturation caused by cocaine. In summary, pre-extinction treatment with simvastatin facilitates cocaine extinction and prevents cocaine relapse with brain lipidome remodeling.
Subject(s)
Animals , Male , Mice , Brain , Cocaine , Conditioning, Operant , Extinction, Psychological , Lipidomics , Simvastatin/therapeutic useABSTRACT
Nonalcoholic fatty liver disease (NAFLD) has become one of the most prominent causes of chronic liver diseases and malignancies. However, few therapy has been approved. Radix Bupleuri (RB) is the most frequently used herbal medicine for the treatment of liver diseases. In the current study, we aim to systemically evaluate the therapeutic effects of saikosaponin A (SSa) and saikosaponin D (SSd), the major bioactive monomers in RB, against NAFLD and to investigate the underlying mechanisms. Our results demonstrated that both SSa and SSd improved diet-induced NAFLD. Integrative lipidomic and transcriptomic analysis revealed that SSa and SSd modulated glycerolipid metabolism by regulating related genes, like
ABSTRACT
O presente trabalho investigou se a exposição em períodos precoces da vida à ração com alto teor de gordura animal altera o risco de câncer de mama na vida adulta em ratas. Ratas mães foram expostas à ração com alto teor de gordura (ATG) à base de banha de porco (60 % de energia proveniente de gordura) ou uma dieta controle AIN93G (16 % de energia proveniente de gordura) durante a gestação ou gestação e lactação. A prole feminina com 7 semanas de idade foi induzida a carcinogênese mamária com o carcinógeno 7,12-dimeti-benz[a]antraceno. Comparado à prole do grupo controle, observou-se menor suscetibilidade à carcinogênese mamária na prole do grupo de ratas prenhas submetidas à ração ATG durante a gestação (menor incidência de neoplasias, multiplicidade e peso das neoplasias) ou gestação e lactação (menor multiplicidade). Prole feminina de ratas exposta à ração ATG durante a gestação apresentou menor crescimento da árvore epitelial mamária, proliferação celular (Ki67) e expressão de NFkB p65 e maior expressão de p21 e níveis globais de H3K9me3 na glândula mamária. Além disso, esta apresentou uma tendência na redução da razão Rank/Rankl (p=0,09) e níveis de progesterona sérica (p=0,07). Glândula mamária da prole feminina do grupo exposto à ração ATG durante a gestação e lactação apresentou menor número de TEBs, crescimento da árvore epitelial e razão BCL-2/BAX e maiores níveis de leptina em comparação à prole do grupo controle. Análise de lipidômica das glândulas mamárias revelou que exposição à ração ATG especificamente durante a gestação apresentou pequenos efeitos no perfil de ácidos graxos na prole feminina, enquanto que a exposição à essa ração durante a gestação e lactação promoveu menor concentração de ácidos graxos saturados (exceto ácido esteárico) e maior concentração de ácidos graxos polinsaturados da série n-6, monoinsaturados e ácido linoleico conjugado (CLA). De acordo com análise de dependência de redes diferencial (DDN) dos genes diferentemente expressos pela análise de "microarray" exposição à ração ATG em períodos precoces da vida altera a rede transcricional da glândula mamária na vida adulta. Especificamente, ratas expostas à ração ATG somente durante o período fetal apresentou aumento da expressão de Hrh1 e Repin1 em comparação ao controle. A prole exposta à ração durante o período fetal e lactacional apresentou maior e menor expressão de Stra6 e Tlr1 em comparação ao contole, respectivamente e menor expressão de Crkrs em comparação à prole exposta à ração somente durante o período fetal. Nossos dados confirmam que o risco de câncer de mama da prole pode ser programado pela alimentação materna. No entanto, ao contrário do que se esperava, exposição a altos níveis de gordura animal no início da vida diminuiu a suscetibilidade ao câncer de mama na vida adulta. Dentre os possíveis mecanismos envolvidos nessa proteção encontram-se a modulação da morfologia e perfil lipídico da glândula mamária, redução da proliferação celular e aumento dos níveis proteicos de reguladores do ciclo celular, modulação de marcas epigenéticas como H3K9me3, modulação da expressão gênica global com alteração de redes de sinalização, bem como regulação de vias de sinalização específicas como RANK/RANKL/NFκB. Porém esses mecanismos são dependentes do tempo e período de exposição
The present study investigated whether early life exposure to high levels of animal fat changes breast cancer risk in adulthood in rats. Dams consumed a lard-based high-fat (HF) diet (60% fat-derived energy) or an AIN93G control diet (16% fat-derived energy) during gestation or gestation and lactation. Their 7-week-old female offspring were exposed to 7,12-dimethylbenz[a]anthracene to induce mammary tumors. Compared to the control offspring, significantly lower susceptibility to mammary cancer development was observed in the offspring of dams fed on HF diet during gestation (lower tumor incidence, multiplicity and weight), or gestation and lactation (lower tumor multiplicity only). Mammary epithelial elongation, cell proliferation (Ki67), and expression of NFkB p65 were significantly lower, and p21 expression and global H3K9me3 levels were higher in the mammary glands of rats exposed to HF lard diet in utero. They also tended to have lower Rank/Rankl ratios (p=0.09) and serum progesterone levels (p=0.07) than control offspring. In the mammary glands of offspring of dams consuming the HF diet during both gestation and lactation, the number of terminal end buds, epithelial elongation and the BCL-2/BAX ratio were significantly lower, and serum leptin levels were higher than in the controls. Lipidomic analysis on mammary glands showed that exposure to a lard-based HF diet only during gestation had little effects on fatty acids profile on offspring, whereas this exposure during gestation and lactation promoted significant changes on the offspring's mammary glands. In general, it decreased SFA (except for stearic acid) and increased n-6 PUFA, MUFA and CLA concentrations in mammary gland. According to Differential dependency network (DDN), analysis of genes differently expressed by microarray, exposure to HF diet during early life changes the transcriptional network of the mammary gland in adulthood. Specifically, rats exposed to HF diet only during the fetal period showed increased expression of Hrh1 e Repin1 compared to the control. The offspring exposed to the HF diet in utero and nursing had higher and lower expression of Stra6 and Tlr1, respectively, compared to the control and lower expression of Crkrs compared to the offspring exposed only in utero. Our data confirm that the breast cancer risk of offspring can be programmed by maternal dietary intake. However, contrary to our expectation, exposure to high levels of lard during early life decreased later susceptibility to breast cancer. The mechanisms involve modulation of mammary gland's morphology and lipid profile, decrease of cell proliferation and increase of cell cycle regulators, modulation of epigenetics marks as H3K9me3, modulation of global gene expression with alteration of transcriptional network and RANK/RANKL/NFκB pathway. However, these mechanisms are dependent on the duration and period of exposure