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Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073458


Cytotoxic CD4+ T cells (CD4 CTL) are terminally differentiated T helper cells that contribute to autoimmune diseases, such as multiple sclerosis. We developed a novel triple co-culture transwell assay to study mutual interactions between CD4 CTL, conventional TH cells, and regulatory T cells (Tregs) simultaneously. We show that, while CD4 CTL are resistant to suppression by Tregs in vitro, the conditioned medium of CD4 CTL accentuates the suppressive phenotype of Tregs by upregulating IL-10, Granzyme B, CTLA-4, and PD-1. We demonstrate that CD4 CTL conditioned medium skews memory TH cells to a TH17 phenotype, suggesting that the CD4 CTL induce bystander polarization. In our triple co-culture assay, the CD4 CTL secretome promotes the proliferation of TH cells, even in the presence of Tregs. However, when cell-cell contact is established between CD4 CTL and TH cells, the proliferation of TH cells is no longer increased and Treg-mediated suppression is restored. Taken together, our results suggest that when TH cells acquire cytotoxic properties, these Treg-resistant CD4 CTL affect the proliferation and phenotype of conventional TH cells in their vicinity. By creating such a pro-inflammatory microenvironment, CD4 CTL may favor their own persistence and expansion, and that of other potentially pathogenic TH cells, thereby contributing to pathogenic responses in autoimmune disorders.

Doenças Autoimunes/imunologia , Proliferação de Células , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adulto , Antígeno CTLA-4/imunologia , Feminino , Granzimas/imunologia , Humanos , Interleucina-10/imunologia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/citologia , Células Th17/citologia
Sci Rep ; 9(1): 4908, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894635


Activation of liver X receptors (LXRs) by synthetic agonists was found to improve cognition in Alzheimer's disease (AD) mice. However, these LXR agonists induce hypertriglyceridemia and hepatic steatosis, hampering their use in the clinic. We hypothesized that phytosterols as LXR agonists enhance cognition in AD without affecting plasma and hepatic triglycerides. Phytosterols previously reported to activate LXRs were tested in a luciferase-based LXR reporter assay. Using this assay, we found that phytosterols commonly present in a Western type diet in physiological concentrations do not activate LXRs. However, a lipid extract of the 24(S)-Saringosterol-containing seaweed Sargassum fusiforme did potently activate LXRß. Dietary supplementation of crude Sargassum fusiforme or a Sargassum fusiforme-derived lipid extract to AD mice significantly improved short-term memory and reduced hippocampal Aß plaque load by 81%. Notably, none of the side effects typically induced by full synthetic LXR agonists were observed. In contrast, administration of the synthetic LXRα activator, AZ876, did not improve cognition and resulted in the accumulation of lipid droplets in the liver. Administration of Sargassum fusiforme-derived 24(S)-Saringosterol to cultured neurons reduced the secretion of Aß42. Moreover, conditioned medium from 24(S)-Saringosterol-treated astrocytes added to microglia increased phagocytosis of Aß. Our data show that Sargassum fusiforme improves cognition and alleviates AD pathology. This may be explained at least partly by 24(S)-Saringosterol-mediated LXRß activation.

Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/genética , Receptores X do Fígado/genética , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/genética , Placa Amiloide/tratamento farmacológico , Sargassum/química , Estigmasterol/análogos & derivados , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina/farmacologia , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Cognição/efeitos dos fármacos , Cognição/fisiologia , Meios de Cultivo Condicionados/farmacologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Genes Reporter , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Receptores X do Fígado/agonistas , Receptores X do Fígado/metabolismo , Luciferases/genética , Luciferases/metabolismo , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Memória de Curto Prazo/fisiologia , Camundongos , Camundongos Transgênicos , Microglia/citologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fármacos Neuroprotetores/isolamento & purificação , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/fisiopatologia , Transdução de Sinais , Estigmasterol/isolamento & purificação , Estigmasterol/farmacologia , Tiazóis/farmacologia
Anim Cogn ; 16(5): 845-50, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23740471


Interest in cognitive research in pigs is increasing, but little is known about the impact of environmental conditions on pigs' cognitive capabilities. The present study investigated the effect of environmental enrichment on cognitive performance of pigs in a holeboard spatial task, in which they had to discriminate four baited buckets out of 16. Pigs (n = 32) were either housed in stimulus-poor, barren pens, or in larger pens enriched with rooting substrates. Pigs were subjected to 30 holeboard trials. Both working memory (WM), that is, the ratio (baited visits/total number of (re)visits to baited buckets), and reference memory (RM), that is, the ratio ((re)visits to baited buckets/total number of visits to all buckets), improved over trials. WM scores were higher in pigs from enriched pens than in pigs from barren pens. Housing did not affect RM scores. Personality type of the pigs, as assessed early in life using a backtest, did not affect WM or RM. In conclusion, housing conditions of pigs did not affect reference memory, but environmental enrichment improved working memory of pigs in a spatial discrimination task. Based on the findings of this study, we suggest that cognitive functioning of pigs may be impaired under commonly used housing conditions.

Discriminação Psicológica , Memória de Curto Prazo , Reconhecimento Psicológico , Percepção Espacial , Sus scrofa/psicologia , Animais , Meio Ambiente
Reproduction ; 142(6): 907-14, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21984747


This study assessed the effect of pre-natal social stress and post-natal pain on the reproductive development of young (approximately day 40) pigs. Male pigs carried by sows that were stressed by mixing with unfamiliar older sows for two 1-week periods during mid-pregnancy had lower plasma testosterone (0.54 vs 0.86 ng/ml, S.E.D.=0.11; P=0.014) and oestradiol (E(2); 22.9 vs 38.7 pg/ml, S.E.D.=7.80; P=0.021) concentrations compared with males carried by unstressed control sows. Although there was no effect of pre-natal stress on female E(2) concentrations, female pigs carried by stressed sows had fewer primordial ovarian follicles (log -4.32/µm(2) vs -4.00/µm(2), s.e.d.=0.136; P=0.027). Tail amputation on day 3 after birth reduced E(2) concentrations in female (4.78 vs 6.84 pg/ml, s.e.d.=0.86; P=0.03) and in male (25.6 vs 34.9 pg/ml, S.E.D.=3.56; P=0.021) pigs and reduced both testis weight (0.09% of body weight vs 0.10% of body weight, S.E.D.=0.003; P=0.01) and the percentage of proliferating Leydig cells (1.97 vs 2.12, S.E.D.=0.114; P=0.036) compared with sham-amputated littermate controls. There was a significant (P=0.036) interaction between the effects of pre-natal stress and post-natal pain on testicular expression of the steroidogenic enzyme 17α-hydroxylase, such that amputation increased expression in pigs born to control sows, but reduced expression in animals born to stressed sows. This study shows that stressful procedures associated with routine animal husbandry can disrupt the developing reproductive axis.

Criação de Animais Domésticos , Dor/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal , Desenvolvimento Sexual , Estresse Psicológico , Animais , Feminino , Masculino , Gravidez , Caracteres Sexuais , Estresse Fisiológico , Suínos