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1.
J Pers Med ; 12(8)2022 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-36013213

RESUMO

Evaluation of the effect of three dimensional (3D) coronary plaque characteristics derived from two dimensional (2D) invasive angiography images (ICA) on coronary flow determined by TIMI frame count (TFC) in acute coronary syndrome (ACS) has not been thoroughly investigated. A total of 71 patients with STEMI, and 73 with NSTEMI were enrolled after primary angioplasty. Pre- and post-PCI TFCs were obtained. From 2D images, 3D reconstruction was performed of the culprit vessel, and multiple plaque parameters were measured. In STEMI, the average post-PCI frame count decreased significantly, resulting in better flow. With regards to 2/3D parameters, no differences were found between the STEMI and NSTEMI groups. The 3D parameters in the subgroup with an increase with at least three frames resulting in worsening post-PCI flow were compared to parameters of the patients with improved or significantly not change flow (delta frame count < 3), and greater minimal luminal diameter and area was found in the worsening (increased) frame group. In STEMI 2/3D, parameters showed no correlation with worsening flow, whereas in NSTEMI, greater minimal luminal diameter and area correlated with decreased flow. We can conclude that certain 2/3D parameters can predict slower flow in ACS, resulting in the use of GP IIb/IIIa receptor blocker.

2.
J Neurochem ; 159(3): 525-542, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34379806

RESUMO

Sepsis-associated encephalopathy (SAE) represents diverse cerebral dysfunctions in response to pathogen-induced systemic inflammation. Peripheral exposure to lipopolysaccharide (LPS), a component of the gram-negative bacterial cell wall, has been extensively used to model systemic inflammation. Our previous studies suggested that LPS led to hippocampal neuron death and synaptic destruction in vivo. However, the underlying roles of activated microglia in these neuronal changes remained unclear. Here, LPS from two different bacterial strains (Salmonella enterica or E. coli) were compared and injected in 14- to 16-month-old mice and evaluated for neuroinflammation and neuronal integrity in the hippocampus at 7 or 63 days post-injection (dpi). LPS injection resulted in persistent neuroinflammation lasting for seven days and a subsequent normalisation by 63 dpi. Of note, increases in proinflammatory cytokines, microglial morphology and microglial mean lysosome volume were more pronounced after E. coli LPS injection than Salmonella LPS at 7 dpi. While inhibitory synaptic puncta density remained normal, excitatory synaptic puncta were locally reduced in the CA3 region of the hippocampus at 63 dpi. Finally, we provide evidence that excitatory synapses coated with complement factor 3 (C3) decreased between 7 dpi and 63 dpi. Although we did not find an increase of synaptic pruning by microglia, it is plausible that microglia recognised and eliminated these C3-tagged synapses between the two time points of investigation. Since a region-specific decline of CA3 synapses has previously been reported during normal ageing, we postulate that systemic inflammation may have accelerated or worsened the CA3 synaptic changes in the ageing brain.


Assuntos
Envelhecimento/patologia , Região CA3 Hipocampal/patologia , Inflamação/patologia , Sinapses/patologia , Animais , Feminino , Imuno-Histoquímica , Lipopolissacarídeos , Camundongos , Camundongos Endogâmicos C57BL , Microglia/patologia , Salmonella , Sepse/patologia , Sinaptossomos/patologia
3.
Sensors (Basel) ; 21(3)2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33535491

RESUMO

As demonstrated by earlier studies, pre-hospital triage with trans-telephonic electrocardiogram (TTECG) and direct referral for catheter therapy shows great value in the management of out-of-hospital chest pain emergencies. It does not only improve in-hospital mortality in ST-segment elevation myocardial infarction, but it has also been identified as an independent predictor of higher in-hospital survival rate. Since TTECG-facilitated triage shortens both transport time and percutaneous coronary intervention (PCI)-related procedural time intervals, it was hypothesized that even high-risk patients with acute coronary syndrome (ACS) and cardiogenic shock (CS) might also benefit from TTECG-based triage. Here, we decided to examine our database for new triage- and left ventricular (LV) function-related parameters that can influence in-hospital mortality in ACS complicated by CS. ACS patients were divided into two groups, namely, (1) hospital death patients (n = 77), and (2) hospital survivors (control, n = 210). Interestingly, TTECG-based consultation and triage of CS and ACS patients were confirmed as significant independent predictors of lower hospital mortality risk (odds ratio (OR) 0.40, confidence interval (CI) 0.21-0.76, p = 0.0049). Regarding LV function and blood chemistry, a good myocardial reperfusion after PCI (high area at risk (AAR) blush score/AAR LV segment number; OR 0.85, CI 0.78-0.98, p = 0.0178) and high glomerular filtration rate (GFR) value at the time of hospital admission (OR 0.97, CI 0.96-0.99, p = 0.0042) were the most crucial independent predictors of a decreased risk of in-hospital mortality in this model. At the same time, a prolonged time interval between symptom onset and hospital admission, successful resuscitation, and higher peak creatine kinase activity were the most important independent predictors for an increased risk of in-hospital mortality. In ACS patients with CS, (1) an early TTECG-based teleconsultation and triage, as well as (2) good myocardial perfusion after PCI and a high GFR value at the time of hospital admission, appear as major independent predictors of a lower in-hospital mortality rate.


Assuntos
Síndrome Coronariana Aguda , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Síndrome Coronariana Aguda/diagnóstico , Mortalidade Hospitalar , Humanos , Fatores de Risco , Choque Cardiogênico/diagnóstico , Resultado do Tratamento
4.
Geroscience ; 43(1): 19-29, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33469835

RESUMO

Coronavirus disease 2019 (COVID-19) has a high mortality in elderly patients with pre-existing cardiovascular diseases. The cellular receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the angiotensin-converting enzyme 2 (ACE2), thereby implicating a link between cardiovascular diseases and SARS-CoV-2 susceptibility. Aortic stenosis (AS) represents a chronic inflammatory state with severe cardiovascular complications in the elderly, a prime condition for COVID-19 mortality. The circulating ACE2 levels were measured in 111 patients with severe AS and compared to patients with hypertension and healthy individuals. About 4 times higher circulating ACE2 activity was found in patients with severe AS than in hypertensives or healthy individuals (88.3 ± 61.6., n = 111, 20.6 ± 13.4, n = 540, and 16.1 ± 7.4 mU/L, n = 46, respectively). Patients with severe AS were older than patients with hypertension (80 ± 6 years vs. 60 ± 15 years, P < 0.05). Serum ACE2 activity correlated negatively with the left ventricular ejection fraction, aortic root area, TAPSE, and positively with the right ventricular systolic pressure, cardiac diameters in patients with AS. In contrast, circulating ACE2 activity was independent of the blood pressure, peak flow velocity at the aortic root, kidney function (GFR), and inflammatory state (CRP). We found no effect of RAAS inhibitory drugs on the serum ACE2 activity in this group of patients. Our results illustrate circulating ACE2 as a potential interface between chronic inflammation, cardiovascular disease, and COVID-19 susceptibility. Elderly patients with AS have markedly elevated ACE2 levels together with altered left and right ventricular functions, which may pose higher risks during COVID-19. Our clinical data do not support a role for RAAS inhibitors in regulating circulating ACE2 levels.


Assuntos
Estenose da Valva Aórtica , COVID-19 , Idoso , Enzima de Conversão de Angiotensina 2 , Biomarcadores , Humanos , Pessoa de Meia-Idade , Peptidil Dipeptidase A , Sistema Renina-Angiotensina , SARS-CoV-2 , Volume Sistólico , Função Ventricular Esquerda
5.
Sci Rep ; 10(1): 3821, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32123224

RESUMO

The neuronal regulation of metabolic and behavioral responses to different diets and feeding regimens is an important research area. Herein, we investigated if the opioid peptide dynorphin modulates feeding behavior and metabolism. Mice lacking dynorphin peptides (KO) were exposed to either a normal diet (ND) or a high-fat diet (HFD) for a period of 12 weeks. Additionally, mice had either time-restricted (TR) or ad libitum (AL) access to food. Body weight, food intake and blood glucose levels were monitored throughout the 12-week feeding schedule. Brain samples were analyzed by immunohistochemistry to detect changes in the expression levels of hypothalamic peptides. As expected, animals on HFD or having AL access to food gained more weight than mice on ND or having TR access. Unexpectedly, KO females on TR HFD as well as KO males on AL ND or AL HFD demonstrated a significantly increased body weight gain compared to the respective WT groups. The calorie intake differed only marginally between the genotypes: a significant difference was present in the female ND AL group, where dynorphin KO mice ate more than WT mice. Although female KO mice on a TR feeding regimen consumed a similar amount of food as WT controls, they displayed significantly higher levels of blood glucose. We observed significantly reduced levels of hypothalamic orexigenic peptides neuropeptide Y (NPY) and orexin-A in KO mice. This decrease became particularly pronounced in the HFD groups and under AL condition. The kappa opiod receptor (KOR) levels were higher after HFD compared to ND feeding in the ventral pallidum of WT mice. We hypothesize that HFD enhances dynorphin signaling in this hedonic center to maintain energy homeostasis, therefore KO mice have a more pronounced phenotype in the HFD condition due to the lack of it. Our data suggest that dynorphin modulates metabolic changes associated with TR feeding regimen and HFD consumption. We conclude that the lack of dynorphin causes uncoupling between energy intake and body weight gain in mice; KO mice maintained on HFD become overweight despite their normal food intake. Thus, using kappa opioid receptor agonists against obesity could be considered as a potential treatment strategy.


Assuntos
Encéfalo/metabolismo , Dinorfinas/metabolismo , Comportamento Alimentar , Animais , Glicemia/metabolismo , Peso Corporal , Dieta Hiperlipídica/efeitos adversos , Dinorfinas/deficiência , Dinorfinas/genética , Feminino , Técnicas de Inativação de Genes , Masculino , Camundongos
6.
Mamm Genome ; 31(1-2): 30-48, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32060626

RESUMO

The collaborative cross (CC) is a large panel of mouse-inbred lines derived from eight founder strains (NOD/ShiLtJ, NZO/HILtJ, A/J, C57BL/6J, 129S1/SvImJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Here, we performed a comprehensive and comparative phenotyping screening to identify phenotypic differences and similarities between the eight founder strains. In total, more than 300 parameters including allergy, behavior, cardiovascular, clinical blood chemistry, dysmorphology, bone and cartilage, energy metabolism, eye and vision, immunology, lung function, neurology, nociception, and pathology were analyzed; in most traits from sixteen females and sixteen males. We identified over 270 parameters that were significantly different between strains. This study highlights the value of the founder and CC strains for phenotype-genotype associations of many genetic traits that are highly relevant to human diseases. All data described here are publicly available from the mouse phenome database for analyses and downloads.


Assuntos
Camundongos Endogâmicos/genética , Fenótipo , Animais , Camundongos de Cruzamento Colaborativo/genética , Bases de Dados Genéticas , Feminino , Estudos de Associação Genética , Genótipo , Masculino , Camundongos , Locos de Características Quantitativas , Especificidade da Espécie
7.
J Telemed Telecare ; 26(4): 216-222, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-30526257

RESUMO

INTRODUCTION: The transtelephonic electrocardiogram has been shown to have a great value in the management of out-of-hospital chest pain emergencies. In our previous study it not only improved the pre-hospital medical therapy and time to intervention, but also the in-hospital mortality in ST-segment elevation myocardial infarction. It was hypothesised that the higher in-hospital survival rate could be due to improved transtelephonic electrocardiogram-based pre-hospital management (electrocardiogram interpretation and teleconsultation) and consequently, better coronary perfusion of patients at the time of hospital admission. To test this hypothesis, our database of ST-segment elevation myocardial infarction patients was evaluated retrospectively for predictors (including transtelephonic electrocardiogram) that may influence in-hospital survival. METHODS AND RESULTS: The ST-segment elevation myocardial infarction patients were divided into two groups, namely (a) hospital death patients (n = 49) and (b) hospital survivors (control, n = 726). Regarding pre-hospital medical management, the transtelephonic electrocardiogram-based triage (odds ratio 0.48, confidence interval 0.25-0.92, p = 0.0261) and the administration of optimal pre-hospital medical therapy (acetylsalicylic acid and/or clopidogrel and glycoprotein IIb/IIIa inhibitor) were the most important independent predictors for a decreased risk in our model. At the same time, age, acute heart failure (Killip class >2), successful pre-hospital resuscitation and total occlusion of the infarct-related coronary artery before percutaneous coronary intervention were the most important independent predictors for an increased risk of in-hospital mortality. DISCUSSION: In ST-segment elevation myocardial infarction patients, (a) an early transtelephonic electrocardiogram-based teleconsultation and triage, (b) optimal pre-hospital antithrombotic medical therapy and (c) the patency and better perfusion of the infarct-related coronary artery on hospital admission are important predictors of a lower in-hospital mortality rate.


Assuntos
Eletrocardiografia/estatística & dados numéricos , Mortalidade Hospitalar , Intervenção Coronária Percutânea/estatística & dados numéricos , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Estudos Retrospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Triagem/organização & administração
8.
J Neurochem ; 155(6): 650-661, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-31872431

RESUMO

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder causing memory loss, language problems and behavioural disturbances. AD is associated with the accumulation of fibrillar amyloid-ß (Aß) and the formation of neurofibrillary tau tangles. Fibrillar Aß itself represents a danger-associated molecular pattern, which is recognized by specific microglial receptors. One of the key players is formation of the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome, whose activation has been demonstrated in AD patient brains and transgenic animal models of AD. Here, we investigated whether Aß oligomers or protofibrils that represent lower molecular aggregates prior to Aß deposition are able to activate the NLRP3 inflammasome and subsequent interleukin-1 beta (IL-1ß) release by microglia. In our study, we used Aß preparations of different sizes: small oligomers and protofibrils of which the structure was confirmed by atomic force microscopy. Primary microglial cells from C57BL/6 mice were treated with the respective Aß preparations and NLRP3 inflammasome activation, represented by caspase-1 cleavage, IL-1ß production, and apoptosis-associated speck-like protein containing a CARD speck formation was analysed. Both protofibrils and low molecular weight Aß aggregates induced a significant increase in IL-1ß release. Inflammasome activation was confirmed by apoptosis-associated speck-like protein containing a CARD speck formation and detection of active caspase-1. The NLRP3 inflammasome inhibitor MCC950 completely inhibited the Aß-induced immune response. Our results show that the NLRP3 inflammasome is activated not only by fibrillar Aß aggregates as reported before, but also by lower molecular weight Aß oligomers and protofibrils, highlighting the possibility that microglial activation by these Aß species may initiate innate immune responses in the central nervous system prior to the onset of Aß deposition. Cover Image for this issue: https://doi.org/10.1111/jnc.14773.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Amiloide/metabolismo , Microglia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Animais Recém-Nascidos , Sobrevivência Celular/fisiologia , Inflamassomos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
9.
J Inherit Metab Dis ; 42(5): 839-849, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31111503

RESUMO

Triosephosphate isomerase (TPI) deficiency is a fatal genetic disorder characterized by hemolytic anemia and neurological dysfunction. Although the enzyme defect in TPI was discovered in the 1960s, the exact etiology of the disease is still debated. Some aspects indicate the disease could be caused by insufficient enzyme activity, whereas other observations indicate it could be a protein misfolding disease with tissue-specific differences in TPI activity. We generated a mouse model in which exchange of a conserved catalytic amino acid residue (isoleucine to valine, Ile170Val) reduces TPI specific activity without affecting the stability of the protein dimer. TPIIle170Val/Ile170Val mice exhibit an approximately 85% reduction in TPI activity consistently across all examined tissues, which is a stronger average, but more consistent, activity decline than observed in patients or symptomatic mouse models that carry structural defect mutant alleles. While monitoring protein expression levels revealed no evidence for protein instability, metabolite quantification indicated that glycolysis is affected by the active site mutation. TPIIle170Val/Ile170Val mice develop normally and show none of the disease symptoms associated with TPI deficiency. Therefore, without the stability defect that affects TPI activity in a tissue-specific manner, a strong decline in TPI catalytic activity is not sufficient to explain the pathological onset of TPI deficiency.


Assuntos
Anemia Hemolítica Congênita não Esferocítica/patologia , Erros Inatos do Metabolismo dos Carboidratos/patologia , Domínio Catalítico/genética , Triose-Fosfato Isomerase/deficiência , Triose-Fosfato Isomerase/genética , Anemia Hemolítica Congênita não Esferocítica/enzimologia , Animais , Comportamento Animal , Erros Inatos do Metabolismo dos Carboidratos/enzimologia , Modelos Animais de Doenças , Estabilidade Enzimática , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Multimerização Proteica
10.
J Pain Res ; 12: 635-647, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30804682

RESUMO

BACKGROUND: Neuropathic pain resulting from peripheral nerve lesions is a common medical condition, but current analgesics are often insufficient. The identification of key molecules involved in pathological pain processing is a prerequisite for the development of new analgesic drugs. Hyperexcitability of nociceptive DRG-neurons due to regulation of voltage-gated ion-channels is generally assumed to contribute strongly to neuropathic pain. There is increasing evidence, that T-type Ca2+-currents and in particular the Cav3.2 T-type-channel isoform play an important role in neuropathic pain, but experimental results are contradicting. PURPOSE: To clarify the role of T-type Ca2+-channels and in particular the Cav3.2 T-type-channel isoform in neuropathic pain. METHODS: The effect of partial sciatic nerve ligation (PNL) on pain behavior and the properties of T-type-currents in nociceptive DRG-neurons was tested in wild-type and Cav3.2-deficient mice. RESULTS: In wild-type mice, PNL of the sciatic nerve caused neuropathic pain and an increase of T-type Ca2+-currents in capsaicin-responsive neurons, while capsaicin-unresponsive neurons were unaffected. Pharmacological experiments revealed that this upregulation was due to an increase of a Ni2+-resistant Ca2+-current component, inconsistent with Cav3.2 up-regulation. Moreover, following PNL Cav3.2-deficient mice showed neuropathic pain behavior and an increase of T-Type Ca2+-currents indistinguishable to that of PNL treated wild-type mice. CONCLUSION: These data suggest that PNL induces an upregulation of T-Type Ca2+-currents in capsaicin-responsive DRG-neurons mediated by an increase of a Ni2+-insensitive current component (possibly Cav3.1 or Cav3.3). These findings provide relevance for the development of target specific analgesic drugs.

11.
Biochim Biophys Acta Mol Basis Dis ; 1865(9): 2083-2093, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30557699

RESUMO

Mutations in the X chromosomal tRNA 2'­O­methyltransferase FTSJ1 cause intellectual disability (ID). Although the gene is ubiquitously expressed affected individuals present no consistent clinical features beyond ID. In order to study the pathological mechanism involved in the aetiology of FTSJ1 deficiency-related cognitive impairment, we generated and characterized an Ftsj1 deficient mouse line based on the gene trapped stem cell line RRD143. Apart from an impaired learning capacity these mice presented with several statistically significantly altered features related to behaviour, pain sensing, bone and energy metabolism, the immune and the hormone system as well as gene expression. These findings show that Ftsj1 deficiency in mammals is not phenotypically restricted to the brain but affects various organ systems. Re-examination of ID patients with FTSJ1 mutations from two previously reported families showed that several features observed in the mouse model were recapitulated in some of the patients. Though the clinical spectrum related to Ftsj1 deficiency in mouse and man is variable, we suggest that an increased pain threshold may be more common in patients with FTSJ1 deficiency. Our findings demonstrate novel roles for Ftsj1 in maintaining proper cellular and tissue functions in a mammalian organism.


Assuntos
Modelos Animais de Doenças , Deficiência Intelectual/etiologia , Deficiência Intelectual Ligada ao Cromossomo X/genética , Metiltransferases/fisiologia , Mutação , Proteínas Nucleares/genética , tRNA Metiltransferases/fisiologia , Animais , Comportamento Animal , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Família , Feminino , Deficiência Intelectual/patologia , Masculino , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dor Nociceptiva/etiologia , Dor Nociceptiva/patologia , Proteínas Nucleares/metabolismo , tRNA Metiltransferases/genética , tRNA Metiltransferases/metabolismo
12.
Biochem Biophys Res Commun ; 503(4): 2770-2777, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30100055

RESUMO

Heterozygous missense mutations in the human VCP gene cause inclusion body myopathy associated with Paget disease of bone and fronto-temporal dementia (IBMPFD) and amyotrophic lateral sclerosis (ALS). The exact molecular mechanisms by which VCP mutations cause disease manifestation in different tissues are incompletely understood. In the present study, we report the comprehensive analysis of a newly generated R155C VCP knock-in mouse model, which expresses the ortholog of the second most frequently occurring human pathogenic VCP mutation. Heterozygous R155C VCP knock-in mice showed decreased plasma lactate, serum albumin and total protein concentrations, platelet numbers, and liver to body weight ratios, and increased oxygen consumption and CD8+/Ly6C + T-cell fractions, but none of the typical human IBMPFD or ALS pathologies. Breeding of heterozygous mice did not yield in the generation of homozygous R155C VCP knock-in animals. Immunoblotting showed identical total VCP protein levels in human IBMPFD and murine R155C VCP knock-in tissues as compared to wild-type controls. However, while in human IBMPFD skeletal muscle tissue 70% of the total VCP mRNA was derived from the mutant allele, in R155C VCP knock-in mice only 5% and 7% mutant mRNA were detected in skeletal muscle and brain tissue, respectively. The lack of any obvious IBMPFD or ALS pathology could thus be a consequence of the very low expression of mutant VCP. We conclude that the increased and decreased fractions of the R155C mutant VCP mRNA in man and mice, respectively, are due to missense mutation-induced, divergent alterations in the biological half-life of the human and murine mutant mRNAs. Furthermore, our work suggests that therapy approaches lowering the expression of the mutant VCP mRNA below a critical threshold may ameliorate the intrinsic disease pathology.


Assuntos
Esclerose Lateral Amiotrófica/genética , Demência Frontotemporal/genética , Genes Letais , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação , Miosite de Corpos de Inclusão/genética , Osteíte Deformante/genética , Proteína com Valosina/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Animais , Antígenos Ly/genética , Antígenos Ly/metabolismo , Encéfalo/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Modelos Animais de Doenças , Feminino , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Regulação da Expressão Gênica , Técnicas de Introdução de Genes , Heterozigoto , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Distrofia Muscular do Cíngulo dos Membros/patologia , Miosite de Corpos de Inclusão/metabolismo , Miosite de Corpos de Inclusão/patologia , Osteíte Deformante/metabolismo , Osteíte Deformante/patologia , Transdução de Sinais , Especificidade da Espécie , Proteína com Valosina/metabolismo
13.
PLoS Biol ; 16(4): e2005019, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29659570

RESUMO

Animal welfare requires the adequate housing of animals to ensure health and well-being. The application of environmental enrichment is a way to improve the well-being of laboratory animals. However, it is important to know whether these enrichment items can be incorporated in experimental mouse husbandry without creating a divide between past and future experimental results. Previous small-scale studies have been inconsistent throughout the literature, and it is not yet completely understood whether and how enrichment might endanger comparability of results of scientific experiments. Here, we measured the effect on means and variability of 164 physiological parameters in 3 conditions: with nesting material with or without a shelter, comparing these 2 conditions to a "barren" regime without any enrichments. We studied a total of 360 mice from each of 2 mouse strains (C57BL/6NTac and DBA/2NCrl) and both sexes for each of the 3 conditions. Our study indicates that enrichment affects the mean values of some of the 164 parameters with no consistent effects on variability. However, the influence of enrichment appears negligible compared to the effects of other influencing factors. Therefore, nesting material and shelters may be used to improve animal welfare without impairment of experimental outcome or loss of comparability to previous data collected under barren housing conditions.


Assuntos
Bem-Estar do Animal/ética , Ambiente Controlado , Comportamento de Nidação/fisiologia , Bem-Estar do Animal/economia , Animais , Metabolismo Energético/fisiologia , Feminino , Testes de Função Cardíaca/métodos , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Nociceptividade/fisiologia
14.
Naunyn Schmiedebergs Arch Pharmacol ; 391(4): 455-461, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29445825

RESUMO

Chronic alcohol abuse leads to severe brain damage. Although the underlying neuropathological processes are largely unknown, recent studies show that chronic alcohol consumption leads to neuroinflammation and may result in neurodegeneration and impaired neuronal connectivity. Long-term alcohol consumption promotes the production of pro-inflammatory cytokines, such as TNF-α and IL-1ß, and activates microglia cells in the brain. As it has not yet been investigated to what extent these processes dependent on the duration of alcohol consumption or whether microglia are source of pro-inflammatory cytokines in vivo, this study investigated the expression of the pro-inflammatory cytokine, IL-1ß, in microglia at different time points in mice chronically exposed to alcohol. In the present study, we exposed mice to 2, 6, and 12 months of alcohol consumption, and using immunohistochemistry, analyzed the expression of the microglial marker, Iba1, together with the pro-inflammatory cytokine IL-1ß in several cortical regions. Moreover, we investigated the effect of pro-inflammatory activation of microglia on neuronal density. We found that alcohol drinking progressively enhanced IL-1ß expression in microglia, which was paralleled with an overall increased microglial density after long-term alcohol consumption. However, we did not find changes in the neuronal density or cortical volume after long-term alcohol consumption. These data show that 12 months of alcohol drinking leads to a pro-inflammatory activation of microglia, which may contribute to impaired neuronal connectivity in the cortex. Anti-inflammatory drug treatment during or after chronic alcohol consumption may thus provide a strategy for restoring brain homeostasis.


Assuntos
Etanol/farmacologia , Interleucina-1beta/metabolismo , Microglia/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/metabolismo , Animais , Masculino , Camundongos Endogâmicos C57BL , Microglia/metabolismo
15.
Mol Neurobiol ; 55(6): 4580-4595, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28695538

RESUMO

In neuropsychiatric diseases, such as major depression and anxiety, pathogenic vulnerability is partially dictated by a genetic predisposition. The search continues to define this genetic susceptibility and establish new genetic elements as potential therapeutic targets. The fibroblast growth factors (FGFs) could be interesting in this regard. This family of signaling molecules plays important roles in development while also functioning within the adult. This includes effects on aspects of brain function such as neurogenesis and synapse formation. Of this family, Fgf9 is expressed in the adult brain, but its functional role is less well defined. In this study, we examined the role of Fgf9 in different brain functions by analyzing the behavior of Fgf9 Y162C mutant mice, an Fgf9 allele without the confounding systemic effects of other Fgf9 genetic models. Here, we show that this mutation caused altered locomotor and exploratory reactivity to novel, mildly stressful environments. In addition, mutants showed heightened acoustic startle reactivity as well as impaired social discrimination memory. Notably, there was a substantial decrease in the level of adult olfactory bulb neurogenesis with no difference in hippocampal neurogenesis. Collectively, our findings indicate a role for the Fgf9 Y162C mutation in information processing and perception of aversive situations as well as in social memory. Thus, genetic alterations in Fgf9 could increase vulnerability to developing neuropsychiatric disease, and we propose the Fgf9 Y162C mutant mice as a valuable tool to study the predictive etiological aspects.


Assuntos
Fator 9 de Crescimento de Fibroblastos/genética , Memória , Mutação/genética , Comportamento Social , Análise de Variância , Anestesia , Animais , Ansiedade/genética , Ansiedade/fisiopatologia , Corticosterona/metabolismo , Discriminação Psicológica , Feminino , Hipocampo/patologia , Hipocampo/fisiopatologia , Masculino , Camundongos , Camundongos Mutantes , Atividade Motora , Neurogênese , Bulbo Olfatório/patologia , Bulbo Olfatório/fisiopatologia , Reflexo de Sobressalto , Caracteres Sexuais
16.
PLoS One ; 12(8): e0182754, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28859076

RESUMO

BACKGROUND: Nutrient deprivation during early development has been associated with the predisposition to metabolic disorders in adulthood. Considering its interaction with metabolism, appetite and behavior, the endocannabinoid (eCB) system represents a promising target of developmental programming. METHODS: By cross-fostering and variation of litter size, early postnatal nutrition of CB6F1-hybrid mice was controlled during the lactation period (3, 6, or 10 pups/mother). After weaning and redistribution at P21, all pups received standard chow ad libitum. Gene expression analyses (liver, visceral fat, hypothalamus) were performed at P50, eCB concentrations were determined in liver and visceral fat. Locomotor activity and social behavior were analyzed by means of computer-assisted videotracking. RESULTS: Body growth was permanently altered, with differences for length, weight, body mass index and fat mass persisting beyond P100 (all 3>6>10,p<0.01). This was paralleled by differences in hepatic IGF-I expression (p<0.01). Distinct gene expression patterns for key enzymes of the eCB system were observed in fat (eCB-synthesis: 3>6>10 (DAGLα p<0.05; NAPE-PLD p = 0.05)) and liver (eCB-degradation: 3>6>10 (FAAH p<0.05; MGL p<0.01)). Concentrations of endocannabinoids AEA and 2-AG in liver and visceral fat were largely comparable, except for a borderline significance for higher AEA (liver, p = 0.049) in formerly overfed mice and, vice versa, tendencies (p<0.1) towards lower AEA (fat) and 2-AG (liver) in formerly underfed animals. In the arcuate nucleus, formerly underfed mice tended to express more eCB-receptor transcripts (CB1R p<0.05; CB2R p = 0.08) than their overfed fellows. Open-field social behavior testing revealed significant group differences, with formerly underfed mice turning out to be the most sociable animals (p<0.01). Locomotor activity did not differ. CONCLUSION: Our data indicate a developmental plasticity of somatic growth, behavior and parameters of the eCB system, with long-lasting impact of early postnatal nutrition. Developmental programming of the eCB system in metabolically active tissues, as shown here for liver and fat, may play a role in the formation of the adult cardiometabolic risk profile following perinatal malnutrition in humans.


Assuntos
Endocanabinoides/metabolismo , Fator de Crescimento Insulin-Like I/genética , Estado Nutricional , Hipernutrição/genética , Animais , Peso Corporal , Modelos Animais de Doenças , Feminino , Expressão Gênica/genética , Humanos , Hipotálamo/metabolismo , Gordura Intra-Abdominal/metabolismo , Fígado/metabolismo , Camundongos , Hipernutrição/metabolismo , Hipernutrição/patologia , Gravidez
17.
Nat Commun ; 8(1): 155, 2017 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-28761067

RESUMO

Dietary restriction regimes extend lifespan in various animal models. Here we show that longevity in male C57BL/6J mice subjected to every-other-day feeding is associated with a delayed onset of neoplastic disease that naturally limits lifespan in these animals. We compare more than 200 phenotypes in over 20 tissues in aged animals fed with a lifelong every-other-day feeding or ad libitum access to food diet to determine whether molecular, cellular, physiological and histopathological aging features develop more slowly in every-other-day feeding mice than in controls. We also analyze the effects of every-other-day feeding on young mice on shorter-term every-other-day feeding or ad libitum to account for possible aging-independent restriction effects. Our large-scale analysis reveals overall only limited evidence for a retardation of the aging rate in every-other-day feeding mice. The data indicate that every-other-day feeding-induced longevity is sufficiently explained by delays in life-limiting neoplastic disorders and is not associated with a more general slowing of the aging process in mice.Dietary restriction can extend the life of various model organisms. Here, Xie et al. show that intermittent periods of fasting achieved through every-other-day feeding protect mice against neoplastic disease but do not broadly delay organismal aging in animals.


Assuntos
Envelhecimento , Privação de Alimentos , Longevidade , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL
18.
Dis Model Mech ; 10(8): 981-991, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28645892

RESUMO

MEIS1 encodes a developmental transcription factor and has been linked to restless legs syndrome (RLS) in genome-wide association studies. RLS is a movement disorder leading to severe sleep reduction and has a substantial impact on the quality of life of patients. In genome-wide association studies, MEIS1 has consistently been the gene with the highest effect size and functional studies suggest a disease-relevant downregulation. Therefore, haploinsufficiency of Meis1 could be the system with the most potential for modeling RLS in animals. We used heterozygous Meis1-knockout mice to study the effects of Meis1 haploinsufficiency on mouse behavioral and neurological phenotypes, and to relate the findings to human RLS. We exposed the Meis1-deficient mice to assays of motor, sensorimotor and cognitive ability, and assessed the effect of a dopaminergic receptor 2/3 agonist commonly used in the treatment of RLS. The mutant mice showed a pattern of circadian hyperactivity, which is compatible with human RLS. Moreover, we discovered a replicable prepulse inhibition (PPI) deficit in the Meis1-deficient animals. In addition, these mice were hyposensitive to the PPI-reducing effect of the dopaminergic receptor agonist, highlighting a role of Meis1 in the dopaminergic system. Other reported phenotypes include enhanced social recognition at an older age that was not related to alterations in adult olfactory bulb neurogenesis previously shown to be implicated in this behavior. In conclusion, the Meis1-deficient mice fulfill some of the hallmarks of an RLS animal model, and revealed the role of Meis1 in sensorimotor gating and in the dopaminergic systems modulating it.


Assuntos
Proteína Meis1/metabolismo , Córtex Sensório-Motor/metabolismo , Córtex Sensório-Motor/patologia , Envelhecimento/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Neurônios Dopaminérgicos/metabolismo , Feminino , Ferritinas/sangue , Haploinsuficiência/genética , Ferro/sangue , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Proteína Meis1/deficiência , Neurogênese/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Fenótipo , Inibição Pré-Pulso/efeitos dos fármacos , Receptores Dopaminérgicos/metabolismo , Córtex Sensório-Motor/efeitos dos fármacos , Filtro Sensorial/efeitos dos fármacos , Caracteres Sexuais , Temperatura , Transferrina/metabolismo
19.
Nat Med ; 23(6): 782-787, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28481360

RESUMO

The balance between detrimental, pro-aging, often stochastic processes and counteracting homeostatic mechanisms largely determines the progression of aging. There is substantial evidence suggesting that the endocannabinoid system (ECS) is part of the latter system because it modulates the physiological processes underlying aging. The activity of the ECS declines during aging, as CB1 receptor expression and coupling to G proteins are reduced in the brain tissues of older animals and the levels of the major endocannabinoid 2-arachidonoylglycerol (2-AG) are lower. However, a direct link between endocannabinoid tone and aging symptoms has not been demonstrated. Here we show that a low dose of Δ9-tetrahydrocannabinol (THC) reversed the age-related decline in cognitive performance of mice aged 12 and 18 months. This behavioral effect was accompanied by enhanced expression of synaptic marker proteins and increased hippocampal spine density. THC treatment restored hippocampal gene transcription patterns such that the expression profiles of THC-treated mice aged 12 months closely resembled those of THC-free animals aged 2 months. The transcriptional effects of THC were critically dependent on glutamatergic CB1 receptors and histone acetylation, as their inhibition blocked the beneficial effects of THC. Thus, restoration of CB1 signaling in old individuals could be an effective strategy to treat age-related cognitive impairments.


Assuntos
Envelhecimento/psicologia , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Envelhecimento Cognitivo/psicologia , Disfunção Cognitiva/psicologia , Espinhas Dendríticas/efeitos dos fármacos , Dronabinol/farmacologia , Hipocampo/efeitos dos fármacos , Acetilação/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Disfunção Cognitiva/metabolismo , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/patologia , Endocanabinoides/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/genética , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/patologia , Código das Histonas/efeitos dos fármacos , Memória de Longo Prazo/efeitos dos fármacos , Camundongos , Camundongos Knockout , Receptor CB1 de Canabinoide/efeitos dos fármacos , Receptor CB1 de Canabinoide/genética , Aprendizagem Espacial/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos
20.
Nucleic Acids Res ; 45(6): 3031-3045, 2017 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-27923998

RESUMO

An interplay between the nucleosome binding proteins H1 and HMGN is known to affect chromatin dynamics, but the biological significance of this interplay is still not clear. We find that during embryonic stem cell differentiation loss of HMGNs leads to down regulation of genes involved in neural differentiation, and that the transcription factor OLIG2 is a central node in the affected pathway. Loss of HMGNs affects the expression of OLIG2 as well as that of OLIG1, two transcription factors that are crucial for oligodendrocyte lineage specification and nerve myelination. Loss of HMGNs increases the chromatin binding of histone H1, thereby recruiting the histone methyltransferase EZH2 and elevating H3K27me3 levels, thus conferring a repressive epigenetic signature at Olig1&2 sites. Embryonic stem cells lacking HMGNs show reduced ability to differentiate towards the oligodendrocyte lineage, and mice lacking HMGNs show reduced oligodendrocyte count and decreased spinal cord myelination, and display related neurological phenotypes. Thus, the presence of HMGN proteins is required for proper expression of neural differentiation genes during embryonic stem cell differentiation. Specifically, we demonstrate that the dynamic interplay between HMGNs and H1 in chromatin epigenetically regulates the expression of OLIG1&2, thereby affecting oligodendrocyte development and myelination, and mouse behavior.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular/genética , Epigênese Genética , Proteínas HMGN/fisiologia , Histonas/metabolismo , Proteínas do Tecido Nervoso/genética , Oligodendroglia/citologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular , Células-Tronco Embrionárias/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Proteína HMGN1/genética , Proteína HMGN1/fisiologia , Proteína HMGN2/genética , Proteína HMGN2/fisiologia , Masculino , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Fator de Transcrição 2 de Oligodendrócitos
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