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1.
Sci Rep ; 11(1): 15583, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34341419

RESUMO

Cognitive reserve (CR) is the capability of an individual to cope with a brain pathology through compensatory mechanisms developed through cognitive stimulation by mental and physical activity. Recently, it has been suggested that CR has a protective role against the initiation of substance use, substance consumption patterns and cognitive decline and can improve responses to treatment. However, CR has never been linked to cognitive function and neurotrophic factors in the context of alcohol consumption. The present cross-sectional study aims to evaluate the association between CR (evaluated by educational level), cognitive impairment (assessed using a frontal and memory loss assessment battery) and circulating levels of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) in patients with alcohol use disorder (AUD). Our results indicated that lower educational levels were accompanied by earlier onset of alcohol consumption and earlier development of alcohol dependence, as well as impaired frontal cognitive function. They also suggest that CR, NT-3 and BDNF may act as compensatory mechanisms for cognitive decline in the early stages of AUD, but not in later phases. These parameters allow the identification of patients with AUD who are at risk of cognitive deterioration and the implementation of personalized interventions to preserve cognitive function.

2.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208173

RESUMO

Maternal malnutrition in critical periods of development increases the risk of developing short- and long-term diseases in the offspring. The alterations induced by this nutritional programming in the hypothalamus of the offspring are of special relevance due to its role in energy homeostasis, especially in the endocannabinoid system (ECS), which is involved in metabolic functions. Since astrocytes are essential for neuronal energy efficiency and are implicated in brain endocannabinoid signaling, here we have used a rat model to investigate whether a moderate caloric restriction (R) spanning from two weeks prior to the start of gestation to its end induced changes in offspring hypothalamic (a) ECS, (b) lipid metabolism (LM) and/or (c) hypothalamic astrocytes. Monitorization was performed by analyzing both the gene and protein expression of proteins involved in LM and ECS signaling. Offspring born from caloric-restricted mothers presented hypothalamic alterations in both the main enzymes involved in LM and endocannabinoids synthesis/degradation. Furthermore, most of these changes were similar to those observed in hypothalamic offspring astrocytes in culture. In conclusion, a maternal low caloric intake altered LM and ECS in both the hypothalamus and its astrocytes, pointing to these glial cells as responsible for a large part of the alterations seen in the total hypothalamus and suggesting a high degree of involvement of astrocytes in nutritional programming.


Assuntos
Astrócitos/metabolismo , Restrição Calórica , Endocanabinoides/metabolismo , Hipotálamo/metabolismo , Metabolismo dos Lipídeos , Transdução de Sinais , Animais , Animais Recém-Nascidos , Peso Corporal , Encéfalo/patologia , Feminino , Regulação da Expressão Gênica , Gliose/genética , Gliose/patologia , Inflamação/genética , Inflamação/patologia , Metabolismo dos Lipídeos/genética , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Transdução de Sinais/genética
3.
Brain Struct Funct ; 226(7): 2243-2264, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34236532

RESUMO

Preclinical studies on the effects of abrupt cessation of selective serotonin reuptake inhibitors (SSRIs), a medication often prescribed in alcohol use disorder (AUD) patients with depression, results in alcohol consumption escalation after resuming drinking. However, a potential neuroinflammatory component on this escalation remains unexplored despite the immunomodulatory role of serotonin. Here, we utilized a rat model of 14-daily administration of the SSRI fluoxetine (10 mg/kg/day) along alcohol self-administration deprivation to study the effects of fluoxetine cessation on neuroinflammation after resuming alcohol drinking. Microglial morphology and inflammatory gene expression were analyzed in prelimbic cortex, striatum, basolateral amygdala and dorsal hippocampus. Results indicated that alcohol drinking reinstatement increased microglial IBA1 immunoreactivity and altered morphometric features of activated microglia (fractal dimension, lacunarity, density, roughness, and cell area, perimeter and circularity). Despite alcohol reinstatement, fluoxetine cessation modified microglial morphology in a brain region-specific manner, resulting in hyper-ramified (spatial complexity of branching), reactive (lower heterogeneity and circularity)-like microglia. We also found that microglial cell area correlated with changes in mRNA expression of chemokines (Cx3cl1/fractalkine, Cxcl12/SDF1α, Ccl2/MCP1), cytokines (IL1ß, IL6, IL10) and the innate immune toll-like receptor 4 (TLR4) in dorsal hippocampus. Specifically, TLR4 correlated with microglial spatial complexity assessed by fractal dimension in striatum, suggesting a role in process branching. These findings suggest that alcohol drinking reinstatement after fluoxetine treatment cessation disturbs microglial morphology and reactive phenotype associated with a TLR4/inflammatory response to alcohol in a brain region-specific manner, facts that might contribute to alcohol-induced damage through the promotion of escalation of alcohol drinking behavior.

4.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065168

RESUMO

Increasing evidence links metabolic disorders with neurodegenerative processes including Alzheimer's disease (AD). Late AD is associated with amyloid (Aß) plaque accumulation, neuroinflammation, and central insulin resistance. Here, a humanized AD model, the 5xFAD mouse model, was used to further explore food intake, energy expenditure, neuroinflammation, and neuroendocrine signaling in the hypothalamus. Experiments were performed on 6-month-old male and female full transgenic (Tg5xFAD/5xFAD), heterozygous (Tg5xFAD/-), and non-transgenic (Non-Tg) littermates. Although histological analysis showed absence of Aß plaques in the hypothalamus of 5xFAD mice, this brain region displayed increased protein levels of GFAP and IBA1 in both Tg5xFAD/- and Tg5xFAD/5xFAD mice and increased expression of IL-1ß in Tg5xFAD/5xFAD mice, suggesting neuroinflammation. This condition was accompanied by decreased body weight, food intake, and energy expenditure in both Tg5xFAD/- and Tg5xFAD/5xFAD mice. Negative energy balance was associated with altered circulating levels of insulin, GLP-1, GIP, ghrelin, and resistin; decreased insulin and leptin hypothalamic signaling; dysregulation in main metabolic sensors (phosphorylated IRS1, STAT5, AMPK, mTOR, ERK2); and neuropeptides controlling energy balance (NPY, AgRP, orexin, MCH). These results suggest that glial activation and metabolic dysfunctions in the hypothalamus of a mouse model of AD likely result in negative energy balance, which may contribute to AD pathogenesis development.


Assuntos
Doença de Alzheimer/metabolismo , Metabolismo Energético/fisiologia , Hipotálamo/metabolismo , Doenças Metabólicas/metabolismo , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas Amiloidogênicas/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Polipeptídeo Inibidor Gástrico/metabolismo , Grelina/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Insulina/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Placa Amiloide/metabolismo , Resistina/metabolismo
5.
Chem Biodivers ; 18(7): e2100085, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34046999

RESUMO

Neolentinus lepideus is a fungus consumed by rural communities in Central America and Asia due to its rich flavor; however, little information on its chemical composition is available. With this in mind, the objective of this work was to determine the content of vitamin E and C, ergosterol, and phenolic compounds of this fungus, as well as its antioxidant capacity. The quantified bioactive compounds were two isoforms of vitamin E, highlighting α-tocopherol (3370.35 mg/100 g dry weight, DW) and ergosterol (11.70 mg/100 g DW). The total phenolic content was 164.80 mg gallic acid equivalents/100 g, and nine phenolic compounds were identified (protocatechuic, p-hydroxybenzoic, caffeic, vanillic, ferulic, salicylic, p-anisic, trans-cinnamic acids, and scopoletin). The highest antioxidant capacity was detected in the lipophilic extract with TEAC (27688 µmoles Trolox equivalents/100 g). These results suggest that lipophilic compounds are among the main bioactive compounds in N. lepideus, and they might exhibit the highest radical scavenging properties in non-polar extracts.


Assuntos
Antioxidantes/farmacologia , Basidiomycota/química , Cromanos/antagonistas & inibidores , Antioxidantes/química , Antioxidantes/isolamento & purificação
6.
Biomolecules ; 11(4)2021 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805256

RESUMO

The objective of this study was to investigate structural changes and lignin redistribution in Eucalyptus globulus pre-treated by steam explosion under different degrees of severity (S0), in order to evaluate their effect on cellulose accessibility by enzymatic hydrolysis. Approximately 87.7% to 98.5% of original glucans were retained in the pre-treated material. Glucose yields after the enzymatic hydrolysis of pre-treated material improved from 19.4% to 85.1% when S0 was increased from 8.53 to 10.42. One of the main reasons for the increase in glucose yield was the redistribution of lignin as micro-particles were deposited on the surface and interior of the fibre cell wall. This information was confirmed by laser scanning confocal fluorescence and FT-IR imaging; these microscopic techniques show changes in the physical and chemical characteristics of pre-treated fibres. In addition, the results allowed the construction of an explanatory model for microscale understanding of the enzymatic accessibility mechanism in the pre-treated lignocellulose.


Assuntos
Eucalyptus/metabolismo , Lignina/metabolismo , Celulase/metabolismo , Hidrólise , Lignina/química , Microscopia Confocal , Análise de Componente Principal , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura
7.
Int J Mol Sci ; 22(8)2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33919940

RESUMO

Deficiency of pregnancy-associated plasma protein-A2 (PAPP-A2), an IGF-1 availability regulator, causes postnatal growth failure and dysregulation of bone size and density. The present study aimed to determine the effects of recombinant murine IGF-1 (rmIGF-1) on bone composition and remodeling in constitutive Pappa2 knock-out (ko/ko) mice. To address this challenge, X-ray diffraction (XRD), attenuated total reflection-fourier transform infra-red (ATR-FTIR) spectroscopy and gene expression analysis of members of the IGF-1 system and bone resorption/formation were performed. Pappa2ko/ko mice (both sexes) had reduced body and bone length. Male Pappa2ko/ko mice had specific alterations in bone composition (mineral-to-matrix ratio, carbonate substitution and mineral crystallinity), but not in bone remodeling. In contrast, decreases in collagen maturity and increases in Igfbp3, osteopontin (resorption) and osteocalcin (formation) characterized the bone of Pappa2ko/ko females. A single rmIGF-1 administration (0.3 mg/kg) induced short-term changes in bone composition in Pappa2ko/ko mice (both sexes). rmIGF-1 treatment in Pappa2ko/ko females also increased collagen maturity, and Igfbp3, Igfbp5, Col1a1 and osteopontin expression. In summary, acute IGF-1 treatment modifies bone composition and local IGF-1 response to bone remodeling in mice with Pappa2 deficiency. These effects depend on sex and provide important insights into potential IGF-1 therapy for growth failure and bone loss and repair.


Assuntos
Reabsorção Óssea/genética , Fator de Crescimento Insulin-Like I/genética , Osteogênese/efeitos dos fármacos , Proteína Plasmática A Associada à Gravidez/genética , Animais , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Remodelação Óssea/genética , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/patologia , Proteínas de Transporte/genética , Colágeno Tipo I/genética , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Fator de Crescimento Insulin-Like I/farmacologia , Camundongos , Camundongos Knockout , Osteocalcina/genética , Osteopontina/genética , Caracteres Sexuais
8.
Polymers (Basel) ; 13(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805582

RESUMO

Organoclay nanoparticles (Cloisite® C10A, Cloisite® C15) and their combination with carbon black (N330) were studied as fillers in chloroprene/natural/butadiene rubber blends to prepare nanocomposites. The effect of filler type and load on the physical mechanical properties of nanocomposites was determined and correlated with its structure, compatibility and cure properties using Fourier Transformed Infrared (FT-IR), X-ray Diffraction (XRD), Thermogravimetric Analysis (TGA) and rheometric analysis. Physical mechanical properties were improved by organoclays at 5-7 phr. Nanocomposites with organoclays exhibited a remarkable increase up to 46% in abrasion resistance. The improvement in properties was attributed to good organoclay dispersion in the rubber matrix and to the compatibility between them and the chloroprene rubber. Carbon black at a 40 phr load was not the optimal concentration to interact with organoclays. The present study confirmed that organoclays can be a reinforcing filler for high performance applications in rubber nanocomposites.

9.
Pediatr Obes ; 16(2): e12711, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32856418

RESUMO

BACKGROUND: In obesity adipose tissue undergoes structural re-modelling leading to a chronic low-grade inflammatory state linked to insulin resistance (IR). OBJECTIVE: We aimed to develop a clinically relevant biomarker model for stratifying IR in adolescents with obesity. METHODS: Cytokines [tumour cell derived factor 1α, monocyte chemoattract protein (MCP) 1, eotaxin and fractalkine], growth factors [brain-derived neurotrophic factor, pro-fibrotic platelet-derived growth factor (PDGF-BB) and insulin-like growth factor 1] and biochemical/metabolic factors were analysed in serum of 143 pubertal patients with obesity (50% IR; 50% non-IR) and 33 controls. Factor analysis, correlation, binary logistic regression and receiver operating characteristic analysis were used to evaluate combinations of these biomarkers as possible diagnostic tools for IR. RESULTS: Two biomarker IR models combining levels of triglycerides (TG)/HDL, eotaxin, MCP-1 and PDGF-BB in pubertal patients with obesity of both sexes were defined. Altered levels of MCP-1, eotaxin, and PDGF-BB constitute a main component that determines 27.7% of the variance explaining IR. Growth and inflammatory factors comprise two other components linked to the first, together accounting for 59.2% of the variance determining IR. CONCLUSIONS: PDGF-BB, MCP-1, eotaxin, TG and cholesterol concentrations constitute a solid panel of biomarkers associated with IR in pubertal children with obesity that could be useful in their stratification in a clinical setting for stratification.


Assuntos
Quimiocinas/sangue , Resistência à Insulina , Obesidade Pediátrica/fisiopatologia , Puberdade , Tecido Adiposo/metabolismo , Adolescente , Biomarcadores/sangue , Criança , Estudos Transversais , Análise Fatorial , Feminino , Humanos , Modelos Logísticos , Masculino , Obesidade Pediátrica/sangue , Curva ROC
10.
J Comp Neurol ; 529(8): 1724-1742, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33047300

RESUMO

Adult neurogenesis in rodents is modulated by dopaminergic signaling and inhibited by cocaine. However, the sex-specific role of dopamine D1 and D2 receptors (D1R, D2R) in the deleterious effect of cocaine on adult neurogenesis has not been described yet. Here, we explored sex differences in (a) cell proliferation (5'-bromo-2'-deoxyuridine [BrdU]), (b) neural precursor (nestin), (c) neuronal phenotype (BrdU/ß3-tubulin), and (d) neuronal maturity (NeuN) in the subventricular zone (SVZ) of the lateral ventricles and striatum of mice with genetic deletion (D1-/- , D2-/- ) or pharmacological blockage (SCH23390: 0.1 mg/kg/day/5 days; Raclopride: 0.3 mg/kg/day/5 days) of D1R and D2R, and treated (10 mg/kg/day/5 days) and then challenged (5 mg/kg, 48 hr later) with cocaine. Results indicated that hyperactivity responses to cocaine were absent in D1-/- mice and reduced in SCH23390-treated mice. Activity responses to cocaine were reduced in D2-/- males, but absent in D2-/- females and increased in Raclopride-treated females. D1R deletion blocked the deleterious effect of cocaine on SVZ cell proliferation in males. Cocaine-exposed D1-/- males also had reduced neuronal phenotype of SVZ newborn cells and increased striatal neuronal maturity. D2-/- mice had lower proliferative and neural precursor responses. Cocaine in D2-/- females or coadministered with Raclopride in wild-type females improved SVZ cell proliferation, an effect that positively correlated with plasma brain-derived neurotrophic factor (BDNF) concentrations. In conclusion, the sex-specific D1R and D2R signaling on SVZ cell proliferation, neural progenitor and neuronal maturity is differentially perturbed by cocaine, and BDNF may be required to link D2R to neuroplasticity in cocaine addiction in females.

11.
Sci Rep ; 10(1): 21154, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33273645

RESUMO

Obesity has been firmly established as a major risk factor for common disease states including hypertension, type 2 diabetes mellitus, and chronic kidney disease. Increased body mass index (BMI) contributes to the activation of both the systemic and intra-tubular renin angiotensin systems (RAS), which are in turn associated with increased blood pressure (BP) and kidney damage. In this cross-sectional study, 43 subjects of normal or increased body weight were examined in order to determine the correlation of BMI or body fat mass (BFM) with blood pressure, fasting blood glucose (FBG), and urinary kidney injury markers such as interleukin-18 (IL-18), connective tissue growth factor (CTGF), neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 (KIM-1). Our results showed that: (1) subjects with increased body weight showed significantly higher BP, BFM, total body water and metabolic age; (2) BMI was positively correlated to both systolic (R2 = 0.1384, P = 0.01) and diastolic BP (R2 = 0.2437, P = 0.0008); (3) BFM was positively correlated to DBP (R2 = 0.1232, P = 0.02) and partially correlated to urine protein (R2 = 0.047, P = 0.12) and FBG (R2 = 0.07, P = 0.06); (4) overweight young adults had higher urinary mRNA levels of renin, angiotensinogen, IL-18 and CTGF. These suggest that BMI directly affects BP, kidney injury markers, and the activation of the intra-tubular RAS even in normotensive young adults. Given that BMI measurements and urine analyses are non-invasive, our findings may pave the way to developing a new and simple method of screening for the risk of chronic kidney disease in adults.


Assuntos
Biomarcadores/urina , Rim/lesões , Rim/metabolismo , Sobrepeso/genética , Sobrepeso/urina , Sistema Renina-Angiotensina/genética , Tecido Adiposo , Adiposidade , Adolescente , Angiotensinogênio/metabolismo , Glicemia/metabolismo , Pressão Sanguínea , Índice de Massa Corporal , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/urina , Jejum/sangue , Feminino , Humanos , Interleucina-18/genética , Interleucina-18/urina , Rim/fisiopatologia , Modelos Lineares , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Renina/metabolismo , Adulto Jovem
12.
Biology (Basel) ; 9(11)2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33167441

RESUMO

Alzheimer's disease (AD) is the most common form of neurodegeneration and dementia. The endocannabinoid (ECB) system has been proposed as a novel therapeutic target to treat AD. The present study explores the expression of the ECB system, the ECB-related receptor GPR55, and cognitive functions (novel object recognition; NOR) in the 5xFAD (FAD: family Alzheimer's disease) transgenic mouse model of AD. Experiments were performed on heterozygous (HTZ) and homozygous (HZ) 11 month old mice. Protein expression of ECB system components, neuroinflammation markers, and ß-amyloid (Aß) plaques were analyzed in the hippocampus. According to the NOR test, anxiety-like behavior and memory were altered in both HTZ and HZ 5xFAD mice. Furthermore, both animal groups displayed a reduction of cannabinoid (CB1) receptor expression in the hippocampus, which is related to memory dysfunction. This finding was associated with indirect markers of enhanced ECB production, resulting from the combination of impaired monoacylglycerol lipase (MAGL) degradation and increased diacylglycerol lipase (DAGL) levels, an effect observed in the HZ group. Regarding neuroinflammation, we observed increased levels of CB2 receptors in the HZ group that positively correlate with Aß's accumulation. Moreover, HZ 5xFAD mice also exhibited increased expression of the GPR55 receptor. These results highlight the importance of the ECB signaling for the AD pathogenesis development beyond Aß deposition.

13.
Mol Cell Oncol ; 7(5): 1789418, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32944643

RESUMO

High-fat diet (HFD)-induced obesity is associated with increased cancer risk. Long-term feeding with HFD increases the concentration of the saturated fatty acid palmitic acid (PA) in the hypothalamus. We previously showed that, in hypothalamic neuronal cells, exposure to PA inhibits the autophagic flux, which is the whole autophagic process from the synthesis of the autophagosomes, up to their lysosomal fusion and degradation. However, the mechanism by which PA impairs autophagy in hypothalamic neurons remains unknown. Here, we show that PA-mediated reduction of the autophagic flux is not caused by lysosomal dysfunction, as PA treatment does not impair lysosomal pH or the activity of cathepsin B.Instead, PA dysregulates autophagy by reducing autophagosome-lysosome fusion, which correlates with the swelling of endolysosomal compartments that show areduction in their dynamics. Finally, because lysosomes undergo constant dynamic regulation by the small Rab7 GTPase, we investigated the effect of PA treatment on its activity. Interestingly, we found PA treatment altered the activity of Rab7. Altogether, these results unveil the cellular process by which PA exposure impairs the autophagic flux. As impaired autophagy in hypothalamic neurons promotes obesity, and balanced autophagy is required to inhibit malignant transformation, this could affect tumor initiation, progression, and/or response to therapy of obesity-related cancers.

14.
Nutr Neurosci ; : 1-14, 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32954972

RESUMO

Aim: We aimed to investigate whether maternal malnutrition during gestation/lactation induces long-lasting changes on inflammation, lipid metabolism and endocannabinoid signaling in the adult offspring hypothalamus and the role of hypothalamic astrocytes in these changes.Methods: We analyzed the effects of a free-choice hypercaloric palatable diet (P) during (pre)gestation, lactation and/or post-weaning on inflammation, lipid metabolism and endogenous cannabinoid signaling in the adult offspring hypothalamus. We also evaluated the response of primary hypothalamic astrocytes to palmitic acid and anandamide.Results: Postnatal exposure to a P diet induced factors involved in hypothalamic inflammation (Tnfa and Il6) and gliosis (Gfap, vimentin and Iba1) in adult offspring, being more significant in females. In contrast, maternal P diet reduced factors involved in astrogliosis (vimentin), fatty acid oxidation (Cpt1a) and monounsaturated fatty acid synthesis (Scd1). These changes were accompanied by an increase in the expression of the genes for the cannabinoid receptor (Cnr1) and Nape-pld, an enzyme involved in endocannabinoid synthesis, in females and a decrease in the endocannabinoid degradation enzyme Faah in males. These changes suggest that the maternal P diet results in sex-specific alterations in hypothalamic endocannabinoid signaling and lipid metabolism. This hypothesis was tested in hypothalamic astrocyte cultures, where palmitic acid (PA) and the polyunsaturated fatty acid N-arachidonoylethanolamine (anandamide or AEA) were found to induce similar changes in the endocannabinoid system (ECS) and lipid metabolism.Conclusion: These results stress the importance of both maternal diet and sex in long term metabolic programming and suggest a possible role of hypothalamic astrocytes in this process.

15.
Nutrients ; 12(6)2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32575416

RESUMO

Both maternal and early life malnutrition can cause long-term behavioral changes in the offspring, which depends on the caloric availability and the timing of the exposure. Here we investigated in a rat model whether a high-caloric palatable diet given to the mother and/or to the offspring during the perinatal and/or postnatal period might dysregulate emotional behavior and prefrontal cortex function in the offspring at adult age. To this end, we examined both anxiety responses and the mRNA/protein expression of glutamatergic, GABAergic and endocannabinoid signaling pathways in the prefrontal cortex of adult offspring. Male animals born from mothers fed the palatable diet, and who continued with this diet after weaning, exhibited anxiety associated with an overexpression of the mRNA of Grin1, Gria1 and Grm5 glutamate receptors in the prefrontal cortex. In addition, these animals had a reduced expression of the endocannabinoid system, the main inhibitory retrograde input to glutamate synapses, reflected in a decrease of the Cnr1 receptor and the Nape-pld enzyme. In conclusion, a hypercaloric maternal diet induces sex-dependent anxiety, associated with alterations in both glutamatergic and cannabinoid signaling in the prefrontal cortex, which are accentuated with the continuation of the palatable diet during the life of the offspring.


Assuntos
Ansiedade/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Ácido Glutâmico/metabolismo , Córtex Pré-Frontal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Masculino , Gravidez , Ratos , Ratos Wistar , Fatores Sexuais , Tempo
16.
Front Pharmacol ; 11: 730, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32536865

RESUMO

The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that promote ligand-dependent transcription of target genes that regulate energy production, lipid metabolism, and inflammation. The PPAR superfamily comprises three subtypes, PPARα, PPARγ, and PPARß/δ, with differential tissue distributions. In addition to their different roles in the regulation of energy balance and carbohydrate and lipid metabolism, an emerging function of PPARs includes normal homeostasis of intestinal tissue. PPARα activation represses NF-κB signaling, which decreases the inflammatory cytokine production by different cell types, while PPARγ ligands can inhibit activation of macrophages and the production of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and Il-1ß. In this regard, the anti-inflammatory responses induced by PPAR activation might restore physiopathological imbalances associated with inflammatory bowel diseases (IBD). Thus, PPARs and their ligands have important therapeutic potential. This review briefly discusses the roles of PPARs in the physiopathology and therapies of the most important IBDs, ulcerative colitis (UC), and Crohn's disease (CD), as well some new experimental compounds with PPAR activity as promising drugs for IBD treatment.

17.
Br J Pharmacol ; 177(14): 3309-3326, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32167157

RESUMO

BACKGROUND AND PURPOSE: Protective mechanisms of the endogenous cannabinoid system against drug-induced liver injury (DILI) are actively being investigated regarding the differential regulatory role of the cannabinoid CB1 and CB2 receptors in liver fibrogenesis and inflammation. EXPERIMENTAL APPROACH: The 2-arachidonoylglycerol (2-AG)-related signalling receptors and enzymatic machinery, and inflammatory/fibrogenic factors were investigated in the liver of a mouse model of hepatotoxicity induced by acute and repeated overdoses (750 mg·kg-1 ·day-1 ) of paracetamol (acetaminophen), previously treated with selective CB1 (ACEA) and CB2 (JWH015) agonists (10 mg·kg-1 ), or lacking CB1 and CB2 receptors. KEY RESULTS: Acute paracetamol increased the expression of CB2 , ABHD6 and COX-2, while repeated paracetamol increased that of CB1 and COX-2 and decreased that of DAGLß. Both acute paracetamol and repeated paracetamol decreased the liver content of acylglycerols (2-AG, 2-LG and 2-OG). Human liver samples from a patient suffering APAP hepatotoxicity confirmed CB1 and CB2 increments. Acute paracetamol-exposed CB2 KO mice had higher expression of the fibrogenic αSMA and the cytokine IL-6 and lower apoptotic cleaved caspase 3. CB1 deficiency enhanced the repeated APAP-induced increases in αSMA and cleaved caspase 3 and blocked those of CYP2E1, TNF-α, the chemokine CCL2 and the circulating γ-glutamyltransferase (γGT). Although JWH015 reduced the expression of αSMA and TNF-α in acute paracetamol, ACEA increased the expression of cleaved caspase 3 and CCL2 in repeated paracetamol. CONCLUSION AND IMPLICATIONS: The differential role of CB1 versus CB2 receptors on inflammatory/fibrogenic factors related to paracetamol-induced hepatotoxicity should be considered for designing alternative therapies against DILI.


Assuntos
Canabinoides , Doença Hepática Crônica Induzida por Substâncias e Drogas , Acetaminofen/toxicidade , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Monoacilglicerol Lipases , Receptor CB1 de Canabinoide , Receptor CB2 de Canabinoide
18.
Endocrinology ; 160(11): 2717-2718, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31513268
19.
Psychoneuroendocrinology ; 110: 104418, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31491589

RESUMO

BACKGROUND: Obesity is a low-grade inflammation condition that facilitates the development of numerous comorbidities and the dysregulation of brain homeostasis. Additionally, obesity also causes distinct behavioral alterations both in humans and rodents. Here, we investigated the effect of inducible genetic deletion of the cannabinoid type 1 receptor (CB1) in adipocytes (Ati-CB1-KO mice) on obesity-induced memory deficits, depressive-like behavior, neuroinflammation and adult neurogenesis. METHODS: Behavioral, mRNA expression and immunohistochemical studies were performed in Ati-CB1-KO mice and corresponding wild-type controls under standard and high-fat diet. RESULTS: Adipocyte-specific CB1 deletion reversed metabolic disturbances associated with an obese condition confirming previous studies. As compared to obese mice, the metabolic amelioration in Ati-CB1-KO mice was associated with an improvement of mood-related behavior and recognition memory, concomitantly with an increase in cell proliferation in metabolic relevant neurogenic niches in hippocampus and hypothalamus. In mutant mice, these changes were related to an increased neuronal maturation/survival in the hippocampus. Furthermore, CB1 deletion in adipocytes was sufficient to reduce obesity-induced inflammation, gliosis and apoptosis in a brain region-specific manner. CONCLUSIONS: Overall our data provide compelling evidence of the physiological relevance of the adipocyte-brain crosstalk where adipocyte-specific CB1 influences obesity-related cognitive deficits and depression-like behavior, concomitantly with brain remodeling, such as adult neurogenesis and neuroinflammation in the hippocampus and hypothalamus.


Assuntos
Adipócitos/metabolismo , Depressão/genética , Dieta Hiperlipídica/efeitos adversos , Transtornos da Memória/etiologia , Neurite (Inflamação)/genética , Neurogênese/genética , Receptor CB1 de Canabinoide/genética , Células-Tronco Adultas/fisiologia , Animais , Comportamento Animal/fisiologia , Encéfalo/citologia , Encéfalo/fisiologia , Depressão/metabolismo , Deleção de Genes , Masculino , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Transtornos da Memória/psicologia , Camundongos , Camundongos Knockout , Células-Tronco Neurais/fisiologia , Neurite (Inflamação)/metabolismo , Neurite (Inflamação)/patologia , Especificidade de Órgãos/genética , Receptor CB1 de Canabinoide/deficiência , Receptor CB1 de Canabinoide/metabolismo
20.
Rev. cuba. salud pública ; 45(3): e1628, jul.-sep. 2019. tab, graf
Artigo em Espanhol | LILACS, CUMED | ID: biblio-1058441

RESUMO

Introducción: La evaluación de un programa odontológico debe considerar, además de los resultados clínicos, la percepción del paciente en relación a cambios físicos, psicológicos y sociales. En este contexto, la calidad de vida relacionada con salud oral constituye un importante indicador de impacto sanitario y de eficacia de un tratamiento. Objetivo: Evaluar el impacto de la salud oral en la calidad de vida de mujeres que recibieron intervención odontológica en centros de atención primaria de salud de la Región de los Ríos, Chile. Métodos: Estudio cuasi experimental con diseño antes-después de una intervención odontológica en 3907 mujeres, de 15 o más años, en condición de vulnerabilidad con problemas dentales que afectan su calidad de vida relacionada con su salud oral. Se midió a través del cuestionario Perfil de Impacto en Salud Oral (OHIP-7sp). Resultados: Se obtuvo una muestra representativa del 5 por ciento de las participantes (n =137), edad media 48,1 ± 16,1 años. Un 96,4 por ciento percibió que la salud bucal afecta su calidad de vida, valor que desciende a 51,8 por ciento después de la intervención. La variación porcentual fue de 46,3 por ciento. Se evidenció la relación entre calidad de vida y la edad de las participantes. Conclusión: la intervención odontológica tiene un impacto positivo en la calidad de vida relacionada con salud oral de las mujeres, e indirectamente ayuda a mejorar la empleabilidad, porque contribuye, con una mejor salud oral, a fortalecer su autoestima y sus relaciones sociales(AU)


Introduction: The assessment of a dental program should consider, in addition to the clinical results, the perception of the patient in relation to physical, psychological and social changes. In this context, quality of life related to oral health is an important indicator of the health impact and efficacy of a treatment. Objective: To assess the impact of oral health in the quality of life of women who received a dental intervention in primary healthcare centers in the Region of Los Ríos, Chile. Methods: Quasi-experimental study with a before-after design of a dental intervention in 3,907 women aged 15 years or more in vulnerable conditions with dental problems that affect their life quality related to oral health. It was measured by means of the questionnaire Profile of Impact in Oral Health (OHIP-7sp) with previous informed consent, before and after the dental intervention. Results: A representative sample of 5 percent of the participants (n = 137), average age 48.1 ± 16.1 years was obtained. 96,4 percent perceived that oral health affects their quality of life, a value that drops to 51,8 percent after the intervention. The percentage variation was of 46,3 percent being a positive result indicator of program evaluation. It was evidenced a relationship between life quality and the age of the participants. Conclusion: The odontological intervention has a positive impact in quality of life related to women's oral health, and indirectly meets with improving the employability of the beneficiaries by contributing to better oral health, strengthening their self-esteem and social relationships(AU)


Assuntos
Humanos , Feminino , Qualidade de Vida , Grupos de Risco , Saúde Bucal , Saúde da Mulher , Chile
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