Nicotinic α‐7 acetylcholine receptor (nAChRα7) is a critical regulator of cholinergic anti‐inflammatory actions in several diseases, including acute respiratory distress syndrome(ARDS). Given the ...potential importance of α7nAChR as a therapeutic target, we evaluated whether PNU‐282987, an α7nAChR agonist, is effective in protecting the lung against inflammation. We performed intratracheal instillation of LPS to generate acute lung injury (ALI) in C57BL/6 mice. PNU‐282987 treatment, either before or after ALI induction, reduced neutrophil recruitment and IL‐ 1β, TNF‐α, IL‐6, keratinocyte chemoattractant (KC), and IL‐10 cytokine levels in the bronchoalveolar lavage fluid (P> 0.05). In addition, lung NF‐κB phosphorylation decreased, along with collagen fiber deposition and the number of matrix metalloproteinase‐9+ and −2+ cells, whereas the number of tissue inhibitor of metalloproteinase‐1+ cells increased (P < 0.05). PNU‐282987 treatment also reduced lung mRNA levels and the frequency of M1 macrophages, whereas cells expressing the M2‐related markers CD206 and IL‐10 increased, suggesting changes in the macrophage profile. Finally, PNU‐282987 improved lung function in LPS‐treated animals. The collective results suggest that PNU‐282987, anagonist of α7nAChR, reducesLPS‐induced experimental ALI, thus supporting the notion that drugs that act on α7nAChRs should be explored for ARDS treatment in humans.—Pinheiro, N. M., Santana, F. P. R., Almeida, R. R., Guerreiro, M., Martins, M.A., Caperuto, L.C., Câmara, N.O.S., Wensing, L.A., Prado, V. F., Tibério, I. F. L. C., Prado, M.A.M., Prado, C. M. Acute lung injury is reduced by the α7nAChR agonist PNU‐282987 through changes in the macrophage profile. FASEB J. 31, 320–332 (2017) www.fasebj.org
Acetylcholine (ACh), the neurotransmitter of the cholinergic system, regulates inflammation in several diseases including pulmonary diseases. ACh is also involved in a non-neuronal mechanism that ...modulates the innate immune response. Because inflammation and release of pro-inflammatory cytokines are involved in pulmonary emphysema, we hypothesized that vesicular acetylcholine transport protein (VAChT) deficiency, which leads to reduction in ACh release, can modulate lung inflammation in an experimental model of emphysema. Mice with genetical reduced expression of VAChT (VAChT KD
70%) and wild-type mice (WT) received nasal instillation of 50 uL of porcine pancreatic elastase (PPE) or saline on day 0. Twenty-eight days after, animals were evaluated. Elastase instilled VAChT KD
mice presented an increase in macrophages, lymphocytes, and neutrophils in bronchoalveolar lavage fluid and MAC2-positive macrophages in lung tissue and peribronchovascular area that was comparable to that observed in WT mice. Conversely, elastase instilled VAChT KD
mice showed significantly larger number of NF-κB-positive cells and isoprostane staining in the peribronchovascular area when compared to elastase-instilled WT-mice. Moreover, elastase-instilled VAChT-deficient mice showed increased MCP-1 levels in the lungs. Other cytokines, extracellular matrix remodeling, alveolar enlargement, and lung function were not worse in elastase-instilled VAChT deficiency than in elastase-instilled WT-controls. These data suggest that decreased VAChT expression may contribute to the pathogenesis of emphysema, at least in part, through NF-κB activation, MCP-1, and oxidative stress pathways. This study highlights novel pathways involved in lung inflammation that may contribute to the development of chronic obstrutive lung disease (COPD) in cholinergic deficient individuals such as Alzheimer's disease patients.
The brain regulates physiological functions integral to survival. However, the insight into brain neuronal regulation of peripheral immune function and the neuromediator systems and pathways involved ...remains limited. Here, utilizing selective genetic and pharmacological approaches, we studied the role of forebrain cholinergic signaling in the regulation of peripheral immune function and inflammation. Forebrain-selective genetic ablation of acetylcholine release and vagotomy abolished the suppression of serum TNF by the centrally-acting cholinergic drug galantamine in murine endotoxemia. Selective stimulation of acetylcholine action on the M1 muscarinic acetylcholine receptor (M1 mAChR) by central administration of the positive allosteric modulator benzyl quinolone carboxylic acid (BQCA) suppressed serum TNF (TNFα) levels in murine endotoxemia. This effect was recapitulated by peripheral administration of the compound. BQCA also improved survival in murine endotoxemia and these effects were abolished in M1 mAChR knockout (KO) mice. Selective optogenetic stimulation of basal forebrain cholinergic neurons innervating brain regions with abundant M1 mAChR localization reduced serum TNF in endotoxemic mice. These findings reveal that forebrain cholinergic neurons regulate innate immune responses and inflammation, suggesting the possibility that in diseases associated with cholinergic dysfunction, including Alzheimer's disease this anti-inflammatory regulation can be impaired. These results also suggest novel anti-inflammatory approaches based on targeting forebrain cholinergic signaling in sepsis and other disorders characterized by immune dysregulation.
Physiology of the Prion Protein Linden, Rafael; Martins, Vilma R; Prado, Marco A. M ...
Physiological reviews,
04/2008, Letnik:
88, Številka:
2
Journal Article
Recenzirano
Instituto de Biofísica da Universidade Federal do Rio de Janeiro, Rio de Janeiro; Ludwig Institute for Cancer Research, Hospital Alemão Oswaldo Cruz, São Paulo; Programa de Farmacologia Molecular, ...Universidade Federal de Minas Gerais, Belo Horizonte; Centro de Memória, Pontifica Universidade Católica do Rio Grande do Sul, Porto Alegre; Hospital A. C. Camargo and Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
Prion diseases are transmissible spongiform encephalopathies (TSEs), attributed to conformational conversion of the cellular prion protein (PrP C ) into an abnormal conformer that accumulates in the brain. Understanding the pathogenesis of TSEs requires the identification of functional properties of PrP C . Here we examine the physiological functions of PrP C at the systemic, cellular, and molecular level. Current data show that both the expression and the engagement of PrP C with a variety of ligands modulate the following: 1 ) functions of the nervous and immune systems, including memory and inflammatory reactions; 2 ) cell proliferation, differentiation, and sensitivity to programmed cell death both in the nervous and immune systems, as well as in various cell lines; 3 ) the activity of numerous signal transduction pathways, including cAMP/protein kinase A, mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt pathways, as well as soluble non-receptor tyrosine kinases; and 4 ) trafficking of PrP C both laterally among distinct plasma membrane domains, and along endocytic pathways, on top of continuous, rapid recycling. A unified view of these functional properties indicates that the prion protein is a dynamic cell surface platform for the assembly of signaling modules, based on which selective interactions with many ligands and transmembrane signaling pathways translate into wide-range consequences upon both physiology and behavior.
1 Not to be confounded with the laminin receptor precursor, LRP.
Urbanization is an increasingly important dimension of global change, and urban areas likely impose significant natural selection on the species that reside within them. Although many species of ...plants and animals can survive in urban areas, so far relatively little research has investigated whether such populations have adapted (in an evolutionary sense) to their newfound milieu. Even less of this work has taken place in tropical regions, many of which have experienced dramatic growth and intensification of urbanization in recent decades. In the present study, we focus on the neotropical lizard, Anolis cristatellus. We tested whether lizard ecology and morphology differ between urban and natural areas in three of the most populous municipalities on the island of Puerto Rico. We found that environmental conditions including temperature, humidity, and substrate availability differ dramatically between neighboring urban and natural areas. We also found that lizards in urban areas use artificial substrates a large proportion of the time, and that these substrates tend to be broader than substrates in natural forest. Finally, our morphological data showed that lizards in urban areas have longer limbs relative to their body size, as well as more subdigital scales called lamellae, when compared to lizards from nearby forested habitats. This shift in phenotype is exactly in the direction predicted based on habitat differences between our urban and natural study sites, combined with our results on how substrates are being used by lizards in these areas. Findings from a common-garden rearing experiment using individuals from one of our three pairs of populations provide evidence that trait differences between urban and natural sites may be genetically based. Taken together, our data suggest that anoles in urban areas are under significant differential natural selection and may be evolutionarily adapting to their human-modified environments.
The ability to learn Pavlovian associations from environmental cues predicting positive outcomes is critical for survival, motivating adaptive behaviours. This cued-motivated behaviour depends on the ...nucleus accumbens (NAc). NAc output activity mediated by spiny projecting neurons (SPNs) is regulated by dopamine, but also by cholinergic interneurons (CINs), which can release acetylcholine and glutamate via the activity of the vesicular acetylcholine transporter (VAChT) or the vesicular glutamate transporter (VGLUT3), respectively. Here we investigated behavioural and neurochemical changes in mice performing a touchscreen Pavlovian approach task by recording dopamine, acetylcholine, and calcium dynamics from D1- and D2-SPNs using fibre photometry in control, VAChT or VGLUT3 mutant mice to understand how these signals cooperate in the service of approach behaviours toward reward-predicting cues. We reveal that NAc acetylcholine-dopaminergic signalling is continuously updated to regulate striatal output underlying the acquisition of Pavlovian approach learning toward reward-predicting cues.
Human body composition is important in numerous cancer research domains. Our objective was to evaluate clinically accessible methods to achieve practical and precise measures of body composition in ...cancer patients. Dual-energy X-ray absorptiometry (DXA)-based analysis of fat and fat-free mass was performed in 50 cancer patients and compared with bioelectrical impedance analysis (BIA) and with regional computed tomography (CT) images available in the patients' medical records. BIA overestimated or underestimated fat-free mass substantially compared with DXA as the method of reference (up to 9.3 kg difference). Significant changes in fat-free mass over time detected with DXA in a subset of 21 patients (+2.2 ± 3.2%/100 days, p = 0.003), was beyond the limits of detection of BIA. Regional analysis of fat and fat-free tissue at the 3rd lumbar vertebra with either DXA or CT strongly predicted whole-body fat and fat-free mass (r = 0.86-0.94;; p < 0.001). CT images provided detail on specific muscles, adipose tissues and organs, not provided by DXA or BIA. CT presents great practical significance due to the prevalence of these images in patient diagnosis and follow-up, thus marrying clinical accessibility with high precision to quantify specific tissues and to predict whole-body composition.
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Sarcopenic obesity (SO) is assuming a prominent role as a risk factor because of the double metabolic burden derived from low muscle mass (sarcopenia) and excess adiposity (obesity). The ...increase in obesity prevalence rates in older subjects is of concern given the associated disease risks and more limited therapeutic options available in this age group. This review has two main objectives. The primary objective is to collate results from studies investigating the effects of SO on physical and cardio-metabolic functions. The secondary objective is to evaluate published studies for consistency in methodology, diagnostic criteria, exposure and outcome selection. Large between-study heterogeneity was observed in the application of diagnostic criteria and choice of body composition components for the assessment of SO, which contributes to the inconsistent associations of SO with cardio-metabolic outcomes. We propose a metabolic load:capacity model of SO given by the ratio between fat mass and fat free mass, and discuss how this could be operationalised. The concept of regional fat distribution could be incorporated into the model and tested in future studies to advance our understanding of SO as a predictor of risk for cardio-metabolic diseases and physical disability.
Music–color associations are mediated by emotion Palmer, Stephen E.; Schloss, Karen B.; Xu, Zoe ...
Proceedings of the National Academy of Sciences - PNAS,
05/2013, Letnik:
110, Številka:
22
Journal Article
Recenzirano
Odprti dostop
Experimental evidence demonstrates robust cross-modal matches between music and colors that are mediated by emotional associations. US and Mexican participants chose colors that were most/least ...consistent with 18 selections of classical orchestral music by Bach, Mozart, and Brahms. In both cultures, faster music in the major mode produced color choices that were more saturated, lighter, and yellower whereas slower, minor music produced the opposite pattern (choices that were desaturated, darker, and bluer). There were strong correlations (0.89 < r < 0.99) between the emotional associations of the music and those of the colors chosen to go with the music, supporting an emotional mediation hypothesis in both cultures. Additional experiments showed similarly robust cross-modal matches from emotionally expressive faces to colors and from music to emotionally expressive faces. These results provide further support that music-to-color associations are mediated by common emotional associations.
Summary Background Emerging evidence on body composition suggests that sarcopenic obesity (obesity with depleted muscle mass) might be predictive of morbidity and mortality in non-malignant disease ...and also of toxicity to chemotherapy. We aimed to assess the prevalence and clinical implications of sarcopenic obesity in patients with cancer. Methods Between Jan 13, 2004, and Jan 19, 2007, 2115 patients with solid tumours of the respiratory or gastrointestinal tract from a cancer treatment centre serving northern Alberta, Canada, were identified. Available lumbar CT images of the obese patients were analysed for total skeletal muscle cross-sectional area; these values were also used to estimate total body fat-free mass (FFM). Findings Of the 2115 patients initially identified, 325 (15%) were classified as obese (body-mass index BMI ≥30). Of these obese patients, 250 had CT images that met the criteria for analysis. The remaining 75 patients were recorded as without assessable scans. Obese patients had a wide range of muscle mass. Sex-specific cut-offs that defined a significant association between low muscle mass with mortality were ascertained by optimum stratification analysis: 38 (15%) of 250 patients who had assessable CT images that met the criteria for analysis were below these cut-offs and were classified as having sarcopenia. Sarcopenic obesity was associated with poorer functional status compared with obese patients who did not have sarcopenia (p=0·009), and was an independent predictor of survival (hazard ratio HR 4·2 95% CI 2·4–7·2, p<0·0001). Estimated FFM showed a poor association with body-surface area ( r2 =0·37). Assuming that FFM represents the volume of distribution of many cytotoxic chemotherapy drugs, we estimated that individual variation in FFM could account for up to three-times variation in effective volume of distribution for chemotherapy administered per unit body-surface area, in this population. Interpretation This study provides evidence of the great variability of body composition in patients with cancer and links body composition, especially sarcopenic obesity, to clinical implications such as functional status, survival, and potentially, chemotherapy toxicity. Funding Canadian Institutes of Health Research (Ottawa, ON, Canada), Alberta Cancer Board (Edmonton, AB, Canada), and Translational Research Training in Cancer (Edmonton, AB, Canada).
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