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1.
PLoS Genet ; 20(9): e1011093, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39259737

RESUMO

Myocyte Enhancer Factor 2C (MEF2C) is a transcription factor that plays a crucial role in neurogenesis and synapse development. Genetic studies have identified MEF2C as a gene that influences cognition and risk for neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia (SCZ). Here, we investigated the involvement of MEF2C in these phenotypes using human-derived neural stem cells (NSCs) and glutamatergic induced neurons (iNs), which represented early and late neurodevelopmental stages. For these cellular models, MEF2C function had previously been disrupted, either by direct or indirect mutation, and gene expression assayed using RNA-seq. We integrated these RNA-seq data with MEF2C ChIP-seq data to identify dysregulated direct target genes of MEF2C in the NSCs and iNs models. Several MEF2C direct target gene-sets were enriched for SNP-based heritability for intelligence, educational attainment and SCZ, as well as being enriched for genes containing rare de novo mutations reported in ASD and/or developmental disorders. These gene-sets are enriched in both excitatory and inhibitory neurons in the prenatal and adult brain and are involved in a wide range of biological processes including neuron generation, differentiation and development, as well as mitochondrial function and energy production. We observed a trans expression quantitative trait locus (eQTL) effect of a single SNP at MEF2C (rs6893807, which is associated with IQ) on the expression of a target gene, BNIP3L. BNIP3L is a prioritized risk gene from the largest genome-wide association study of SCZ and has a function in mitophagy in mitochondria. Overall, our analysis reveals that either direct or indirect disruption of MEF2C dysregulates sets of genes that contain multiple alleles associated with SCZ risk and cognitive function and implicates neuron development and mitochondrial function in the etiology of these phenotypes.


Assuntos
Cognição , Fatores de Transcrição MEF2 , Neurogênese , Esquizofrenia , Humanos , Transtorno do Espectro Autista/genética , Estudo de Associação Genômica Ampla , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética
2.
Eur J Neurosci ; 60(6): 5234-5248, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39143728

RESUMO

Numerous challenges hinder the development of neuroprotective treatments for Parkinson's disease, with a regularly identified issue being the lack of clinically relevant animal models. Viral vector overexpression of α-synuclein is widely considered the most relevant model; however, this has been limited by high variability and inconsistency. One potential method of optimisation is pairing it with a secondary insult such as FN075, a synthetic molecule demonstrated to accelerate α-synucleinopathy. Thus, the aim of this study was to investigate if sequential infusion of adeno-associated virus (AAV)-α-synuclein and FN075 into the rat brain can replicate α-synucleinopathy, nigrostriatal pathology and motor dysfunction associated with Parkinson's disease. Rats received a unilateral injection of AAV-α-synuclein (or AAV-green fluorescent protein) into two sites in the substantia nigra, followed 4 weeks later by unilateral injection of FN075 (or vehicle) into the striatum. Animals underwent behavioural testing every 4 weeks until sacrifice at 20 weeks, followed by immunohistochemistry assessment post-mortem. As anticipated, AAV-α-synuclein led to extensive overexpression of human α-synuclein throughout the nigrostriatal pathway, as well as elevated levels of phosphorylated and aggregated forms of the protein. However, the sequential administration of FN075 into the striatum did not exacerbate any of the α-synuclein pathology. Furthermore, despite the extensive α-synuclein pathology, neither administration of AAV-α-synuclein nor FN075, alone or in combination, was sufficient to induce dopaminergic degeneration or motor deficits. In conclusion, this approach did not replicate the key characteristics of Parkinson's disease, and further studies are required to create more representational models for testing of novel compounds and treatments for Parkinson's disease.


Assuntos
Corpo Estriado , Dependovirus , alfa-Sinucleína , Animais , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/administração & dosagem , Dependovirus/genética , Corpo Estriado/metabolismo , Corpo Estriado/efeitos dos fármacos , Ratos , Masculino , Modelos Animais de Doenças , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/tratamento farmacológico , Ratos Sprague-Dawley , Vetores Genéticos/administração & dosagem , Substância Negra/metabolismo , Substância Negra/efeitos dos fármacos , Humanos
3.
Brain Behav Immun ; 115: 26-37, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37748567

RESUMO

Recent studies have reported a negative association between exposure to childhood trauma, including physical neglect, and cognitive functioning in patients with schizophrenia. Childhood trauma has been found to influence immune functioning, which may contribute to the risk of schizophrenia and cognitive symptoms of the disorder. In this study, we aimed to test the hypothesis that physical neglect is associated with cognitive ability, and that this association is mediated by a combined latent measure of inflammatory response, and moderated by higher genetic risk for schizophrenia. The study included 279 Irish participants, comprising 102 patients and 177 healthy participants. Structural equation modelling was used to perform mediation and moderation analyses. Inflammatory response was measured via basal plasma levels of IL-6, TNF-α, and CRP, and cognitive performance was assessed across three domains: full-scale IQ, logical memory, and the emotion recognition task. Genetic variation for schizophrenia was estimated using a genome-wide polygenic score based on genome-wide association study summary statistics. The results showed that inflammatory response mediated the association between physical neglect and all measures of cognitive functioning, and explained considerably more variance than any of the inflammatory markers alone. Furthermore, genetic risk for schizophrenia was observed to moderate the direct pathway between physical neglect and measures of non-social cognitive functioning in both patient and healthy participants. However, genetic risk did not moderate the mediated pathway associated with inflammatory response. Therefore, we conclude that the mediating role of inflammatory response and the moderating role of higher genetic risk may independently influence the association between adverse early life experiences and cognitive function in patients and healthy participants.


Assuntos
Experiências Adversas da Infância , Esquizofrenia , Humanos , Estudo de Associação Genômica Ampla , Voluntários Saudáveis , Cognição/fisiologia
4.
Handb Exp Pharmacol ; 276: 291-314, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34783909

RESUMO

Toll-like receptors (TLRs) receptors are responsible for initiation of inflammatory responses by their recognition of molecular patterns present in invading microorganisms (such as bacteria, viruses or fungi) or in molecules released following tissue damage in disease states. Expressed in the intestinal epithelium, they initiate an intracellular signalling cascade in response to molecular patterns resulting in the activation of transcription factors and the release of cytokines, chemokines and vasoactive molecules. Intestinal epithelial cells are exposed to microorganisms on a daily basis and form part of the primary defence against pathogens by using TLRs. TLRs and their accessory molecules are subject to tight regulation in these cells so as to not overreact or react in unnecessary circumstances. TLRs have more recently been associated with chronic inflammatory diseases as a result of inappropriate regulation, this can be damaging and lead to chronic inflammatory diseases such as inflammatory bowel disease (IBD). Targeting Toll-like receptors offers a potential therapeutic approach for IBD. In this review, the current knowledge on the TLRs is reviewed along with their association with intestinal diseases. Finally, compounds that target TLRs in animal models of IBD, clinic trials and their future merit as targets are discussed.


Assuntos
Doenças Inflamatórias Intestinais , Receptores Toll-Like , Animais , Citocinas , Humanos , Imunidade Inata , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mucosa Intestinal , Transdução de Sinais/fisiologia , Receptores Toll-Like/fisiologia , Receptores Toll-Like/uso terapêutico
5.
Immunopharmacol Immunotoxicol ; 44(1): 99-109, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34881658

RESUMO

Background: The intracellular NOD-like receptor (NLR) family of pathogen recognition receptors (PRRa) is involved in initiating the innate immune response of which NOD1 and NOD2 are the best-characterized members. Aberrant expression of NOD1 and NOD2 has been uncovered in a number of chronic inflammatory diseases, such as inflammatory bowel disease and rheumatoid arthritis. However, the mechanism underlying NOD1/NOD2 gene expression regulation is still in its infancy. Epigenetic modifications such as DNA methylation and histone acetylation regulate the expression of genes and alterations in their patterns have been linked to many inflammatory diseases. This study investigated whether epigenetic modifying drugs affect the regulation of NOD1/NOD2 activity and expression. DNA methyltransferase inhibitors have recently been used in the treatment of myelodysplastic syndrome and as combination therapy in cancer but the full extent of their effects has not been quantified.Methods: Pharmacological inhibition of epigenetic enzymes in a human monocytic THP-1 cell line was carried out and NOD1/NOD2 expression and pro-inflammatory responses were quantified.Results: Cells primed with a DNA methyltransferase inhibitor (but not a histone deacetylase [HDAC] inhibitor) were found to be consistently more responsive to NOD1/NOD2 stimulation and had increased basal expression.Conclusion: The novel experimentation carried out here suggests for the first time that NOD1/NOD2 receptor activity and expression in monocytes are possibly regulated directly by DNA methylation.


Assuntos
Proteína Adaptadora de Sinalização NOD1 , Proteína Adaptadora de Sinalização NOD2 , Linhagem Celular , DNA , Humanos , Metiltransferases/metabolismo , Monócitos/metabolismo , Proteínas NLR/metabolismo , Proteína Adaptadora de Sinalização NOD1/genética , Proteína Adaptadora de Sinalização NOD1/metabolismo , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo
6.
Molecules ; 27(2)2022 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-35056822

RESUMO

Since the discovery of α-synuclein as the major component in Lewy bodies, research into this protein in the context of Parkinson's disease pathology has been exponential. Cannabinoids are being investigated as potential therapies for Parkinson's disease from numerous aspects, but still little is known about the links between the cannabinoid system and the pathogenic α-synuclein protein; understanding these links will be necessary if cannabinoid therapies are to reach the clinic in the future. Therefore, the aim of this study was to investigate the time-course of alterations in components of the endocannabinoid system after viral-mediated α-synuclein overexpression in the rat brain. Rats were given unilateral intranigral injections of AAV-GFP or AAV-α-synuclein and sacrificed 4, 8 and 12 weeks later for qRT-PCR and liquid chromatography-mass spectrometry analyses of the endocannabinoid system, in addition to histological visualization of α-synuclein expression along the nigrostriatal pathway. As anticipated, intranigral delivery of AAV-α-synuclein induced widespread overexpression of human α-synuclein in the nigrostriatal pathway, both at the mRNA level and the protein level. However, despite this profound α-synuclein overexpression, we detected no differences in CB1 or CB2 receptor expression in the nigrostriatal pathway; however, interestingly, there was a reduction in the expression of neuroinflammatory markers. Furthermore, there was a reduction in the levels of the endocannabinoid 2-AG and the related lipid immune mediator OEA at week 12 post-surgery, indicating that α-synuclein overexpression triggers dysregulation of the endocannabinoid system. Although this research does show that the endocannabinoid system is impacted by α-synuclein, further research is necessary to more comprehensively understand the link between the cannabinoid system and the α-synuclein aspect of Parkinson's disease pathology in order for cannabinoid-based therapies to be feasible for the treatment of this disease in the coming years.


Assuntos
Corpo Estriado/patologia , Dependovirus/genética , Endocanabinoides/metabolismo , Substância Negra/patologia , alfa-Sinucleína/metabolismo , Animais , Corpo Estriado/metabolismo , Feminino , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismo , Substância Negra/metabolismo , Fatores de Tempo , alfa-Sinucleína/administração & dosagem , alfa-Sinucleína/genética
7.
Brain Behav Immun ; 98: 388-396, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34242739

RESUMO

OBJECTIVE: Exposure to childhood trauma (CT) is associated with cognitive impairment in schizophrenia, and deficits in social cognition in particular. Here, we sought to test whether IL-6 mediated the association between CT and social cognition both directly, and sequentially via altered default mode network (DMN) connectivity. METHODS: Three-hundred-and-eleven participants (104 patients and 207 healthy participants) were included, with MRI data acquired in a subset of n = 147. CT was measured using the childhood trauma questionnaire (CTQ). IL-6 was measured in both plasma and in toll like receptor (TLR) stimulated whole blood. The CANTAB emotion recognition task (ERT) was administered to assess social cognition, and cortical connectivity was assessed based on resting DMN connectivity. RESULTS: Higher IL-6 levels, measured both in plasma and in toll-like receptor (TLR-2) stimulated blood, were significantly correlated with higher CTQ scores and lower cognitive and social cognitive function. Plasma IL-6 was further observed to partly mediate the association between higher CT scores and lower emotion recognition performance (CTQ total: ßindirect -0.0234, 95% CI: -0.0573 to -0.0074; CTQ physical neglect: ßindirect = -0.0316, 95% CI: -0.0741 to -0.0049). Finally, sequential mediation was observed between plasma IL-6 levels and DMN connectivity in mediating the effects of higher CTQ on lower social cognitive function (ßindirect = -0.0618, 95% CI: -0.1523 to -0.285). CONCLUSION: This work suggests that previous associations between CT and social cognition may be partly mediated via an increased inflammatory response. IL-6's association with changes in DMN activity further suggest at least one cortical network via which CT related effects on cognition may be transmitted.


Assuntos
Experiências Adversas da Infância , Esquizofrenia , Encéfalo , Mapeamento Encefálico , Cognição , Humanos , Interleucina-6 , Imageamento por Ressonância Magnética , Testes Neuropsicológicos , Esquizofrenia/diagnóstico por imagem
8.
J Clin Psychol ; 77(1): 241-253, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32783219

RESUMO

OBJECTIVE: This study investigated associations between childhood trauma, parental bonding, and social cognition (i.e., Theory of Mind and emotion recognition) in patients with schizophrenia and healthy adults. METHODS: Using cross-sectional data, we examined the recollections of childhood trauma experiences and social cognitive abilities in 74 patients with schizophrenia and 116 healthy adults. RESULTS: Patients had significantly higher scores compared with healthy participants on childhood trauma, and lower scores on parental bonding and social cognitive measures. Physical neglect was found to be the strongest predictor of emotion recognition impairments in both groups. Optimal parental bonding attenuated the impact of childhood trauma on emotion recognition. CONCLUSION: The present study provides evidence of an association between physical neglect and emotion recognition in patients with schizophrenia and healthy individuals and shows that both childhood trauma and parental bonding may influence social cognitive development. Psychosocial interventions should be developed to prevent and mitigate the long-term effects of childhood adversities.


Assuntos
Esquizofrenia , Teoria da Mente , Adulto , Cognição , Estudos Transversais , Emoções , Humanos , Pais , Cognição Social , Percepção Social
9.
Molecules ; 25(3)2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31973235

RESUMO

Parkinson's disease is a neurodegenerative disorder, the motor symptoms of which are associated classically with Lewy body formation and nigrostriatal degeneration. Neuroinflammation has been implicated in the progression of this disease, by which microglia become chronically activated in response to α-synuclein pathology and dying neurons, thereby acquiring dishomeostatic phenotypes that are cytotoxic and can cause further neuronal death. Microglia have a functional endocannabinoid signaling system, expressing the cannabinoid receptors in addition to being capable of synthesizing and degrading endocannabinoids. Alterations in the cannabinoid system-particularly an upregulation in the immunomodulatory CB2 receptor-have been demonstrated to be related to the microglial activation state and hence the microglial phenotype. This paper will review studies that examine the relationship between the cannabinoid system and microglial activation, and how this association could be manipulated for therapeutic benefit in Parkinson's disease.


Assuntos
Canabinoides/metabolismo , Microglia/metabolismo , Microglia/patologia , Doença de Parkinson/patologia , Doença de Parkinson/terapia , Animais , Humanos , Neuroproteção , Fenótipo
10.
Brain Behav Immun ; 80: 525-535, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31029796

RESUMO

Evidence is accumulating to suggest that viral infections and consequent viral-mediated neuroinflammation may contribute to the etiology of idiopathic Parkinson's disease. Moreover, viruses have been shown to influence α-synuclein oligomerization as well as the autophagic clearance of abnormal intra-cellular proteins aggregations, both of which are key neuropathological events in Parkinson's disease pathogenesis. To further investigate the interaction between viral-mediated neuroinflammation and α-synuclein aggregation in the context of Parkinson's disease, this study sought to determine the impact of viral neuroinflammatory priming on α-synuclein aggregate-induced neuroinflammation and neurotoxicity in the rat nigrostriatal pathway. To do so, male Sprague-Dawley rats were intra-nigrally injected with a synthetic mimetic of viral dsRNA (poly I:C) followed two weeks later by a peptidomimetic small molecule which accelerates α-synuclein fibril formation (FN075). The impact of the viral priming on α-synuclein aggregation-induced neuroinflammation, neurodegeneration and motor dysfunction was assessed. We found that prior administration of the viral mimetic poly I:C significantly exacerbated or precipitated the α-synuclein aggregate induced neuropathological and behavioral effects. Specifically, sequential exposure to the two challenges caused a significant increase in nigral microgliosis (p < 0.001) and astrocytosis (p < 0.01); precipitated a significant degeneration of the nigrostriatal cell bodies (p < 0.05); and precipitated a significant impairment in forelimb kinesis (p < 0.01) and sensorimotor integration (p < 0.01). The enhanced sensitivity of the nigrostriatal neurons to pathological α-synuclein aggregation after viral neuroinflammatory priming further suggests that viral infections may contribute to the etiology and pathogenesis of Parkinson's disease.


Assuntos
Doença de Parkinson/etiologia , Poli I-C/efeitos adversos , alfa-Sinucleína/metabolismo , Animais , Materiais Biomiméticos , Corpo Estriado/metabolismo , Dependovirus/genética , Modelos Animais de Doenças , Vetores Genéticos , Gliose/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/fisiopatologia , Neuroimunomodulação/fisiologia , Neurônios/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Poli I-C/administração & dosagem , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/virologia , Ratos , Ratos Sprague-Dawley , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Sinucleína/fisiologia
11.
Immunopharmacol Immunotoxicol ; 41(5): 527-537, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31505962

RESUMO

Background: Pattern recognition receptors form an essential part of the host defenses against pathogens, in particular in the intestinal epithelium. However, despite their importance relatively little is understood about the regulation of their expression. Increasing evidence suggesting that epigenetic mechanisms such as DNA methylation and histone acetylation have substantial effects on gene expression and regulation. Epigenetic modifying drugs are now used to treat certain cancers but not a lot is known about their effects on the innate immune system. Thus, we set out to examine the role of such drugs in the expression and function of Toll-like receptors. Methods: Using the HCT116 epithelial cell line, we determined the effects of genetic knockout of the DNA methyltransferases enzymes (DNMTs), as well as pharmacological inhibition of the DNMTs and histone deacetylase complexes (HDACs) on TLR responses to their ligands. Results: Our initial results showed that anti-viral responses were affected by changes in the epigenome, with TLR3 responses showing the most dramatic differences. We determined that inhibition of methylation and acetylation inhibited poly I:C induced increases in signaling protein phosphorylation, as well as increases in cytokine mRNA expression and release. We also observed that treatment with epigenetic modifying drugs were leading to large increases in IRF8 expression, a protein that is a known negative regulator of TLR3. When we overexpressed IRF8 in our WT cells we noticed inhibition of poly I:C responses. Conclusion: This research highlighted the potential immunoregulatory role of epigenetic modifying drugs specifically in response to viral stimulation.


Assuntos
Antivirais/farmacologia , Epigênese Genética/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Poli I-C/farmacologia , Receptor 3 Toll-Like/metabolismo , DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA/efeitos dos fármacos , Decitabina/farmacologia , Células Epiteliais/enzimologia , Células Epiteliais/imunologia , Células Epiteliais/virologia , Técnicas de Silenciamento de Genes , Células HCT116 , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/genética , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/enzimologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/virologia , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Receptor 3 Toll-Like/genética , DNA Metiltransferase 3B
12.
Immunology ; 150(3): 237-247, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27706808

RESUMO

Nucleotide-binding oligomerization domain (NOD) -like receptors (NLRs) are a family of 23 receptors known as pattern recognition receptors; they are expressed in many cell types and play a key role in the innate immune response. The NLRs are activated by pathogen-associated molecular patterns, which include structurally conserved molecules present on the surfaces of bacteria. The activation of these NLRs by pathogens results in the downstream activation of signalling kinases and transcription factors, culminating in the transcription of genes coding for pro-inflammatory factors. Expression of NLR is altered in many cellular, physiological and disease states. There is a lack of understanding of the mechanisms by which NLR expression is regulated, particularly in chronic inflammatory states. Genetic polymorphisms and protein interactions are included in such mechanisms. This review seeks to examine the current knowledge regarding the regulation of this family of receptors and their signalling pathways as well as how their expression changes in disease states with particular focus on NOD1 and NOD2 in inflammatory bowel diseases among others.


Assuntos
Doenças Inflamatórias Intestinais/imunologia , Proteínas NLR/metabolismo , Receptores de Reconhecimento de Padrão/metabolismo , Animais , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Proteínas NLR/genética , Polimorfismo Genético , Receptores de Reconhecimento de Padrão/genética , Transdução de Sinais
13.
Immunol Cell Biol ; 94(7): 631-9, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26924642

RESUMO

Toll-like receptors (TLRs) are a family of 13 receptors known as pattern-recognition receptors (PRRs) and have a key role in the innate immune response. The TLRs are activated by pathogen-associated molecular patterns (PAMPs) that are structurally conserved molecules present on the surfaces of bacteria and viruses. The activation of these TLRs by pathogens results in the downstream activation of genes involved in the production of proinflammatory factors. There is a lack of understanding on the mechanisms by which TLR gene expression is regulated. Epigenetics could be one such mechanism, which is concerned with changes in gene expression/products that arise without a change in the nucleotide sequence. These changes are brought about by two main mechanisms, DNA methylation and histone modifications. This review seeks to examine the current knowledge regarding the epigenetic regulation of this family of receptors and their signalling pathways.


Assuntos
Epigênese Genética , Imunidade Inata/genética , Receptores Toll-Like/metabolismo , Animais , Metilação de DNA/genética , Doença/genética , Histonas/metabolismo , Humanos
14.
Exp Physiol ; 101(12): 1477-1491, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27676233

RESUMO

NEW FINDINGS: What is the central question of this study? Does crosstalk exist between leptin and interleukin-6 in colonic enteric neurons, and is this a contributory factor in gastrointestinal dysfunction associated with irritable bowel syndrome? What is the main finding and its importance? Leptin ameliorates the prosecretory and prokinetic effects of the pro-inflammatory cytokine interleukin-6 on rat colon. Leptin also suppresses the neurostimulatory effects of irritable bowel syndrome plasma, which has elevated concentrations of interleukin-6, on enteric neurons. This may indicate a regulatory role for leptin in immune-mediated bowel dysfunction. In addition to its role in regulating energy homeostasis, the adipokine leptin modifies gastrointestinal (GI) function. Indeed, leptin-resistant obese humans and leptin-deficient obese mice exhibit altered GI motility. In the functional GI disorder irritable bowel syndrome (IBS), circulating leptin concentrations are reported to differ from those of healthy control subjects. Additionally, IBS patients display altered cytokine profiles, including elevated circulating concentrations of the pro-inflammatory cytokine interleukin-6 (IL-6), which bears structural homology and similarities in intracellular signalling to leptin. This study aimed to investigate interactions between leptin and IL-6 in colonic neurons and their possible contribution to IBS pathophysiology. The functional effects of leptin and IL-6 on colonic contractility and absorptosecretory function were assessed in organ baths and Ussing chambers in Sprague-Dawley rat colon. Calcium imaging and immunohistochemical techniques were used to investigate the neural regulation of GI function by these signalling molecules. Our findings provide a neuromodulatory role for leptin in submucosal neurons, where it inhibited the stimulatory effects of IL-6. Functionally, this translated to suppression of IL-6-evoked potentiation of veratridine-induced secretory currents. Leptin also attenuated IL-6-induced colonic contractions, although it had little direct effect on myenteric neurons. Calcium responses evoked by IBS plasma in both myenteric and submucosal neurons were also suppressed by leptin, possibly through interactions with IL-6, which is elevated in IBS plasma. As leptin has the capacity to ameliorate the neurostimulatory effects of soluble mediators in IBS plasma and modulated IL-6-evoked changes in bowel function, leptin may have a role in immune-mediated bowel dysfunction in IBS patients.


Assuntos
Colo/efeitos dos fármacos , Colo/metabolismo , Citocinas/metabolismo , Interleucina-6/metabolismo , Leptina/farmacologia , Adolescente , Adulto , Idoso , Animais , Motilidade Gastrointestinal/efeitos dos fármacos , Humanos , Síndrome do Intestino Irritável/metabolismo , Masculino , Pessoa de Meia-Idade , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Adulto Jovem
15.
Curr Opin Gastroenterol ; 31(2): 124-9, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25603403

RESUMO

PURPOSE OF REVIEW: To discuss the recent landmark findings that have increased our understanding not only of the role of the epithelial cell cycle in the homeostasis of the small intestine, but also its relevance to inflammation and cancer. RECENT FINDINGS: Recent data have unveiled novel information on protein interactions directly involved in the cell cycle as well as in the pathways that transduce external environmental signals to the cell cycle. A growing body of the recent evidence confirms the importance of food as well as hormonal regulation in the gut on cell cycle. Information on the contribution of the epithelial microenvironment, including the microbiota, has grown substantially in the recent years as well as on the gene-environment interactions and the multiple epigenetic mechanisms involved in regulating cell-cycle proteins and signalling. Finally, further studies investigating the dysregulation of the cell cycle during inflammation and proliferation have increased our understanding of the pathophysiology of chronic inflammatory diseases and cancer. SUMMARY: This review highlights some of the most recent advances that further emphasize the importance of the cell cycle in the small intestine during homeostasis as well as in inflammation and cancer.


Assuntos
Transformação Celular Neoplásica/imunologia , Células Epiteliais/metabolismo , Homeostase/imunologia , Inflamação/imunologia , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/imunologia , Ciclo Celular , Metilação de DNA , Humanos , Inflamação/patologia , Doenças Inflamatórias Intestinais/patologia , RNA Mensageiro
16.
Brain Behav Immun ; 44: 57-67, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25150006

RESUMO

BACKGROUND: Episodic bouts of abdominal pain and altered bowel habit are characteristic of irritable bowel syndrome (IBS). Although a comprehensive understanding of IBS pathophysiology remains elusive, support is growing for a primary role for immune activation in disease severity as evidenced by altered cytokine profiles in IBS plasma. Additionally, aberrant stimulation of the stress axis is likely to result in altered plasma constituents. METHODS: Whole-mount preparations of submucosal plexus from adult male Sprague Dawley rats were exposed to plasma from IBS patients and healthy controls. Ratiometric calcium imaging recordings were used to measure changes in intracellular calcium ([Ca(2+)]i) as a marker of neuronal excitability. KEY RESULTS: IBS plasma stimulated a robust increase in [Ca(2+)]i (0.09 ± 0.02) whereas plasma from healthy volunteers had little effect (-0.02 ± 0.02, n=24, p<0.001). The neuromodulatory actions of IBS plasma were reduced by pre-neutralisation with anti-interleukin (IL)-6 (p<0.01) but not IL-8, immunoglobulin G or C-reactive protein. Moreover, IBS plasma-evoked responses (0.22 ± 0.06) were inhibited by the corticotrophin releasing factor receptor (CRFR) 1 antagonist, antalarmin (1µM, 0.015 ± 0.02, n=14, p<0.05), but not the CRFR2 antagonist, astressin 2B. Neuronal activation was mediated by ERK/MAPK signalling. CONCLUSIONS: These data provide evidence that factors present in IBS plasma modulate neuronal activity in the submucosal plexus and that this is likely to involve CRFR1 activation and IL-6 signalling. These neuromodulatory actions of stress and immune factors indicate a potential mechanism by which immune activation during periods of stress may lead to symptom flares in IBS.


Assuntos
Síndrome do Intestino Irritável/sangue , Neurônios/metabolismo , Plexo Submucoso/metabolismo , Adulto , Animais , Cálcio/metabolismo , Feminino , Humanos , Interleucina-6/metabolismo , Masculino , Plasma/química , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Receptores de Interleucina-6/metabolismo
17.
Artigo em Inglês | MEDLINE | ID: mdl-37844774

RESUMO

Exposure to early life adversity is associated with both increased risk of developing schizophrenia and poorer performance on measures of social cognitive functioning. In this study, we examined whether interleukin-6 (IL-6) and Corpus Callosum (CC) microstructure mediated the association between childhood physical neglect and social cognition. Fifty-eight patients with a diagnosis of schizophrenia were included. The CANTAB emotion recognition task (unbiased hit rate) was used to assess social cognition. We found that the microstructural organization of the CC significantly mediated the association between physical neglect and emotion recognition. Furthermore, in a sequential mediation analysis that also considered the role of inflammatory response, the association between physical neglect, and lower emotion recognition performance was sequentially mediated by higher IL-6 and lower fractional anisotropy of the CC. This mediating effect of IL-6 was only present when simultaneously considering the effects of CC microstructural organization and remained significant while controlling for the effects of sex, BMI and medication dosage (but not age). Overall, the findings suggest that the association between physical neglect and poorer emotion recognition in schizophrenia occurs, at least in part, via its association with white matter microstructure.


Assuntos
Esquizofrenia , Substância Branca , Humanos , Criança , Corpo Caloso/diagnóstico por imagem , Esquizofrenia/diagnóstico por imagem , Cognição Social , Interleucina-6 , Cognição/fisiologia , Anisotropia
18.
Artigo em Inglês | MEDLINE | ID: mdl-36283512

RESUMO

BACKGROUND: Schizophrenia is a complex psychiatric disorder that includes positive and negative symptoms but also debilitating cognitive deficits. Current pharmacological interventions do not target these deficits. Recent evidence suggests a connection between some inflammatory markers (including C-reactive protein) and cognitive impairment, but did not address other inflammatory markers. In the current study, we try to fill the gap by focusing on the association of Interleukin-6 (IL-6), IL-1ß, Tumor Necrosis Factor-α and CRP with cognitive dysfunction. METHODS: PUBMED and Web of Science databases were searched for all studies published until July 2022. A total of 25 studies were included in an analysis of the association between cognitive performance and variation in IL-6, IL-1ß, TNF-α and CRP. RESULTS: A total of 2398 patients were included in this study. Meta-analyses results showed a significant inverse relationship between performance in five cognitive domains (attention-processing speed, executive function, working memory, verbal and visual learning and memory) and systemic IL-6, IL-1ß, TNF-α and CRP plasma levels in patients with schizophrenia. The meta-analyses results showed a significant decline in the cognitive performances with the evaluated inflammatory markers with effect sizes ranging from -0.136 to -0.181 for IL-6, -0.188 to -0.38 for TNF-α -0.372 to -0.476 for IL-1ß and - 0.168 to -0.311 for CRP. CONCLUSION: Findings from the current study shows that cognitive deficits are reflective of elevated proinflammatory biomarkers (IL-6, IL-1ß, TNF-α and CRP) levels. The results obtained indicate relatedness between inflammation and cognitive decline in patients with schizophrenia. Understanding the underlying pathways between them could have a significant impact on the disease progression and quality of life in schizophrenia patients.


Assuntos
Disfunção Cognitiva , Esquizofrenia , Humanos , Interleucina-6 , Fator de Necrose Tumoral alfa , Qualidade de Vida , Proteína C-Reativa/metabolismo , Biomarcadores , Inflamação
19.
J Psychiatr Res ; 160: 126-136, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36804109

RESUMO

BACKGROUND: Schizophrenia is a major psychiatric disorder with unknown aetiology. Recent evidence suggests a potential role for cytokines in its pathophysiology and that antipsychotic medication may alter this. While the aetiology of schizophrenia remains only partly understood, an altered immune function representing an important avenue of further discovery. In this systematic review and meta-analysis we focus on the specific effects of second generation antipsychotics risperidone and clozapine on inflammatory cytokines. METHODS: A defined systematic search of PubMed and Web of Science databases was performed to identify relevant studies published between Jan 1900 and May 2022. After screening of 2969 papers, 43 studies (27 single-arm and 8 dual-arm) were included that consisted of a total of 1421 patients with schizophrenia in the systematic review. From these, twenty studies (4 dual-arm; 678 patients) had data available on which a meta-analysis could be carried out. RESULTS: Our meta-analysis showed a significant reduction of pro-inflammatory cytokines post-risperidone treatment in the absence of a similar association with clozapine. Subgroup analyses (First episode v chronic) demonstrated that duration of illness influenced the extent of cytokine alteration; risperidone treatment produced significant cytokine changes (lowered IL-6 and TNF-α) in chronic patients but not in first-episode psychosis (FEP) patients. CONCLUSION: Varying treatment effects on cytokines can be observed by the use of different antipsychotic drugs. The cytokine alterations post-treatment are influenced by the specific antipsychotic drugs and patient status. This may explain disease progression in certain patient groups and influence therapeutic choices in the future.


Assuntos
Antipsicóticos , Clozapina , Esquizofrenia , Humanos , Antipsicóticos/uso terapêutico , Esquizofrenia/tratamento farmacológico , Risperidona/uso terapêutico , Clozapina/uso terapêutico , Olanzapina/uso terapêutico , Benzodiazepinas/efeitos adversos , Citocinas , Anti-Inflamatórios
20.
Biomolecules ; 13(8)2023 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-37627253

RESUMO

Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that are ubiquitously expressed in the human body. They protect the brain and central nervous system from self and foreign antigens/pathogens. The immune response elicited by these receptors culminates in the release of cytokines, chemokines, and interferons causing an inflammatory response, which can be both beneficial and harmful to neurodevelopment. In addition, the detrimental effects of TLR activation have been implicated in multiple neurodegenerative diseases such as Alzheimer's, multiple sclerosis, etc. Many studies also support the theory that cytokine imbalance may be involved in schizophrenia, and a vast amount of literature showcases the deleterious effects of this imbalance on cognitive performance in the human population. In this review, we examine the current literature on TLRs, their potential role in the pathogenesis of schizophrenia, factors affecting TLR activity that contribute towards the risk of schizophrenia, and lastly, the role of TLRs and their impact on cognitive performance in schizophrenia.


Assuntos
Esquizofrenia , Humanos , Receptores Toll-Like , Sistema Nervoso Central , Inflamação , Encéfalo , Citocinas
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