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BACKGROUND: Experimental evidence suggests a key role of SIRT1 (silent information regulator 1) in age- and metabolic-related vascular dysfunction. Whether these effects hold true in the human microvasculature is unknown. We aimed to investigate the SIRT1 role in very early stages of age- and obesity-related microvascular dysfunction in humans. METHODS: Ninety-five subjects undergoing elective laparoscopic surgery were recruited and stratified based on their body mass index status (above or below 30 kg/m2) and age (above or below 40 years) in 4 groups: Young Nonobese, Young Obese, Old Nonobese, and Old Obese. We measured small resistance arteries' endothelial function by pressurized micromyography before and after incubation with a SIRT1 agonist (SRT1720) and a mitochondria reactive oxygen species (mtROS) scavenger (MitoTEMPO). We assessed vascular levels of mtROS and nitric oxide availability by confocal microscopy and vascular gene expression of SIRT1 and mitochondrial proteins by qPCR. Chromatin immunoprecipitation assay was employed to investigate SIRT1-dependent epigenetic regulation of mitochondrial proteins. RESULTS: Compared with Young Nonobese, obese and older patients showed lower vascular expression of SIRT1 and antioxidant proteins (FOXO3 [forkhead box protein O3] and SOD2) and higher expression of pro-oxidant and aging mitochondria proteins p66Shc and Arginase II. Old Obese, Young Obese and Old Nonobese groups endothelial dysfunction was rescued by SRT1720. The restoration was comparable to the one obtained with mitoTEMPO. These effects were explained by SIRT1-dependent chromatin changes leading to reduced p66Shc expression and upregulation of proteins involved in mitochondria respiratory chain. CONCLUSIONS: SIRT1 is a novel central modulator of the earliest microvascular damage induced by age and obesity. Through a complex epigenetic control mainly involving p66Shc and Arginase II, it influences mtROS levels, NO availability, and the expression of proteins of the mitochondria respiratory chain. Therapeutic modulation of SIRT1 restores obesity- and age-related endothelial dysfunction. Early targeting of SIRT1 might represent a crucial strategy to prevent age- and obesity-related microvascular dysfunction.
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Arginase , Obesidade , Sirtuína 1 , Doenças Vasculares , Adulto , Arginase/metabolismo , Epigênese Genética , Humanos , Proteínas Mitocondriais/metabolismo , Óxido Nítrico/metabolismo , Obesidade/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Doenças Vasculares/etiologiaRESUMO
PRESTO was established in 2022 and is a concerted effort by leading European experts in the field of P2XRs and extracellular ATP to promote and advance the transition to the clinic of P2XR-targeting therapies. Following the inaugural meeting in Ferrara which set the foundations of the action and generated interest from many groups and institutes, the second meeting covered the preclinical and clinical aspects of P2XRs as a common route in different diseases, recognising the multidisciplinary and collaborative approach required for a number of medical conditions.
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Adenosine A2A receptor (A2AR)-dependent signaling in macrophages plays a key role in the regulation of inflammation. However, the processes regulating A2AR targeting to the cell surface and degradation in macrophages are incompletely understood. For example, the C-terminal domain of the A2AR and proteins interacting with it are known to regulate receptor recycling, although it is unclear what role potential A2AR-interacting partners have in macrophages. Here, we aimed to identify A2AR-interacting partners in macrophages that may effect receptor trafficking and activity. To this end, we performed a yeast two-hybrid screen using the C-terminal tail of A2AR as the "bait" and a macrophage expression library as the "prey." We found that the lysosomal protease cathepsin D (CtsD) was a robust hit. The A2AR-CtsD interaction was validated in vitro and in cellular models, including RAW 264.7 and mouse peritoneal macrophage (IPMΦ) cells. We also demonstrated that the A2AR is a substrate of CtsD and that the blockade of CtsD activity increases the density and cell surface targeting of A2AR in macrophages. Conversely, we demonstrate that A2AR activation prompts the maturation and enzymatic activity of CtsD in macrophages. In summary, we conclude that CtsD is a novel A2AR-interacting partner and thus describe molecular and functional interplay that may be crucial for adenosine-mediated macrophage regulation in inflammatory processes.
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Adenosina , Catepsina D/metabolismo , Receptor A2A de Adenosina , Adenosina/metabolismo , Animais , Proteínas de Transporte/metabolismo , Catepsina D/genética , Macrófagos/metabolismo , Camundongos , Receptor A2A de Adenosina/genética , Receptor A2A de Adenosina/metabolismo , Transdução de SinaisRESUMO
Intestinal barrier alterations represent a primum movens in obesity and related intestinal dysfunctions. However, whether gut barrier remodeling represents prodromal events in obesity before weight gain, metabolic alterations, and systemic inflammation remains unclear. Herein, we examined morphologic changes in the gut barrier in a mouse model of high-fat diet (HFD) since the earliest phases of diet assumption. C57BL/6J mice were fed with standard diet (SD) or HFD for 1, 2, 4, or 8 weeks. Remodeling of intestinal epithelial barrier, inflammatory infiltrate, and collagen deposition in the colonic wall was assessed by histochemistry and immunofluorescence analysis. Obese mice displayed increased body and epididymal fat weight along with increased plasma resistin, IL-1ß, and IL-6 levels after 8 weeks of HFD. Starting from 1 week of HFD, mice displayed (1) a decreased claudin-1 expression in lining epithelial cells, (2) an altered mucus in goblet cells, (3) an increase in proliferating epithelial cells in colonic crypts, (4) eosinophil infiltration along with an increase in vascular P-selectin, and (5) deposition of collagen fibers. HFD intake is associated with morphologic changes in the large bowel at mucosal and submucosal levels. In particular, the main changes include alterations in the mucous layer and intestinal epithelial barrier integrity and activation of mucosal defense-enhanced fibrotic deposition. These changes represent early events occurring before the development of obesity condition that could contribute to compromising the intestinal mucosal barrier and functions, opening the way for systemic dissemination.
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Dieta Hiperlipídica , Obesidade , Animais , Camundongos , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/metabolismo , Aumento de Peso , ColágenoRESUMO
BACKGROUND AND PURPOSE: Changes in gut microbiota composition, enteric inflammation, impairments of the intestinal epithelial barrier and neuroplastic changes in the enteric nervous system have been reported in Parkinson's disease (PD) patients and could contribute to the onset of both neurological and gastrointestinal symptoms. However, their mutual interplay has rarely been investigated. This study evaluated, in an integrated manner, changes in faecal microbiota composition, morphofunctional alterations of colonic mucosal barrier and changes of inflammatory markers in blood and stools of PD patients. METHODS: Nineteen PD patients and nineteen asymptomatic subjects were enrolled. Blood lipopolysaccharide binding protein (LBP, marker of altered intestinal permeability) and interleukin-1ß (IL-1ß) levels, as well as stool IL-1ß and tumour necrosis factor (TNF) levels, were evaluated. Gut microbiota analysis was performed. Epithelial mucins, collagen fibres, claudin-1 and S100-positive glial cells as markers of an impairment of the intestinal barrier, mucosal remodelling and enteric glial activation were evaluated on colonic mucosal specimens collected during colonoscopy. RESULTS: Faecal microbiota analysis revealed a significant difference in the α-diversity in PD patients compared to controls, while no differences were found in the ß-diversity. Compared to controls, PD patients showed significant chenags in plasma LBP levels, as well as faecal TNF and IL-1ß levels. The histological analysis showed a decrease in epithelial neutral mucins and claudin-1 expression and an increased expression of acidic mucins, collagen fibres and S100-positive glial cells. CONCLUSIONS: Parkinson's disease patients are characterized by enteric inflammation and increased intestinal epithelial barrier permeability, as well as colonic mucosal barrier remodelling, associated with changes in gut microbiota composition.
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Quorum sensing was first described as the communication process bacteria employ to coordinate changes in gene expression and therefore, their collective behavior in response to population density. Emerging new evidence suggests that quorum sensing can also contribute to the regulation of immune cell responses. Quorum sensing might be achieved by the ability of immune cells to perceive the density of their own populations or those of other cells in their environment; responses to alterations in cell density might then be coordinated via changes in gene expression and protein signaling. Quorum sensing mechanisms can regulate T and B cell as well as macrophage function. We posit that perturbations in quorum sensing may undermine the balance between diverse immune cell populations and predispose the host to immune abnormalities.
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Sistema Imunitário/imunologia , Percepção de Quorum/imunologia , Animais , HumanosRESUMO
Quorum sensing indicates a communication process between bacteria based on a coordinate variation in gene expression aimed at coordinating a collective comportment related to the bacterial population density. Increasing pieces of evidence pointed out that a quorum-sensing system can be a regulatory program also used in the immune field to organize the density of the various immune cell populations and to calibrate their responses. In particular, such equilibrium is achieved by the ability of immune cells to perceive the density of their own populations or those of other cells in their environment, through the release of several mediators able to finely shape the cell density via coordinated changes in gene expression and protein signaling. In this regard, adenosine displays the typical characteristics of a mediator involved in the regulation of quorum sensing, thus suggesting a putative role of this nucleoside in shaping the balance between diverse immune cell populations.
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Adenosina , Percepção de Quorum , Transdução de SinaisRESUMO
AIM: Obesity is associated with glomerular hyperfiltration which may precede the development of overt renal damage. Few studies evaluated the link between inflammasome signalling and hyperfiltration. The aim is to evaluate the relationship between IL1-ß/Caspase-1, insulin sensitivity and hyperfiltration in subjects with severe obesity, before and after weight loss. METHODS: Forty-six patients with BMI > 35 kg/m2 , without type-2-diabetes or hypertension, were evaluated at baseline and 6 months after bariatric surgery with oral glucose tollerance test, bioimpedance analysis and blood tests. The eGFR was calculated according to EPIcr-cys formula and insulin sensitivity by Oral Glucose Insulin Sensitivity. IL-1ß/Caspase-1 were measured with the ELISA-kit. HF was defined as eGFR ≥ 140 ml/min (non-indexed for BSA). RESULTS: Sixteen subjects at baseline had hyperfiltration, with a higher insulin resistance, BMI, lean mass and plasma levels of IL-1ß/Caspase-1. After surgery, there was a reduction in BMI and improvement in insulin resistance in all patients. However, in 8 of 16 patients hyperfiltration persisted and IL-1ß/Caspase-1 levels did not decrease (3.22 ± 0.79 vs. 3.13 ± 1.03 and 23.7 ± 12.1 vs. 20.6 ± 9.1, pre vs. post, pg/ml), while cytokines normalized in all the other patients in parallel with the eGFR. In a logistic regression model, correcting for the main covariates, lean mass and IL-1ß before surgery (p = .01 and p = .03, respectively), were the only predictors of hyperfiltration. CONCLUSION: Weight loss is effective in reducing hyperfiltration in most, but not all patients. Hyperfiltration remains unchanged in subjects who do not have a reduction in IL-1ß/Caspase-1, suggesting a pathogenetic role of the inflammasome signalling in the early stages of nephropathy.
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Resistência à Insulina , Obesidade Mórbida , Insuficiência Renal Crônica , Caspases , Taxa de Filtração Glomerular , Glucose , Humanos , Inflamassomos , Obesidade Mórbida/complicações , Obesidade Mórbida/diagnóstico , Obesidade Mórbida/cirurgia , Redução de PesoRESUMO
Immune-mediated inflammatory diseases (IMIDs) encompass a wide range of seemingly unrelated conditions, such as multiple sclerosis, rheumatoid arthritis, psoriasis, inflammatory bowel diseases, asthma, chronic obstructive pulmonary disease, and systemic lupus erythematosus. Despite differing etiologies, these diseases share common inflammatory pathways, which lead to damage in primary target organs and frequently to a plethora of systemic effects as well. The purinergic signaling complex comprising extracellular nucleotides and nucleosides and their receptors, the P2 and P1 purinergic receptors, respectively, as well as catabolic enzymes and nucleoside transporters is a major regulatory system in the body. The purinergic signaling complex can regulate the development and course of IMIDs. Here we provide a comprehensive review on the role of purinergic signaling in controlling immunity, inflammation, and organ function in IMIDs. In addition, we discuss the possible therapeutic applications of drugs acting on purinergic pathways, which have been entering clinical development, to manage patients suffering from IMIDs.
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Inflamação/tratamento farmacológico , Inflamação/imunologia , Agonistas Purinérgicos/farmacologia , Antagonistas Purinérgicos/farmacologia , Purinas/metabolismo , Receptores Purinérgicos/metabolismo , Animais , Humanos , Inflamação/metabolismo , Terapia de Alvo Molecular , Purinas/imunologia , Receptores Purinérgicos/imunologia , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Literature suggests that unhealthy body mass index is a risk factor for adverse clinical outcomes. OBJECTIVES: To study the association between unhealthy body mass index and morbidity and mortality after trauma using the 2016 American College of Surgeons Trauma Quality Improvement Program database. METHODS: A retrospective review was conducted comparing the normal weight control group to the underweight, overweight, obese, severely obese, and morbidly obese groups for differences in demographic factors, injury severity score, comorbidities, length of stay, and complications. RESULTS: Underweight, overweight, obese, severely obese, and morbidly obese body mass indexes, in comparison to normal weight body mass index, were associated with a higher probability of developing at least one complication after trauma. Additionally, we observed a J-shaped curve when analyzing body mass index and mortality, suggesting that both high and low body mass indexes are positively associated with mortality. In fact, morbidly obese patients had the highest mortality rate, followed by underweight patients (p < .001). Interestingly, however, multivariate logistic regression demonstrated that, compared with normal weight body mass index, overweight and obese body mass indexes were independently associated with 9.6% and 10.5% lower odds of mortality, respectively (p < .001 and p = .001). CONCLUSION: Irrespective of preexisting comorbidities, injury severity score, and mechanism of injury, underweight, overweight, obese, severely obese, and morbidly obese body mass indexes were independently associated with higher risks of morbidity, whereas overweight and obese body mass indexes were associated with lower mortality risks. These findings emphasize the complex relationship between body mass index and clinical outcomes for trauma patients.
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Obesidade Mórbida , Índice de Massa Corporal , Hospitalização , Humanos , Morbidade , Obesidade Mórbida/complicações , Obesidade Mórbida/epidemiologia , Magreza/complicações , Magreza/epidemiologiaRESUMO
Growing evidence points out the importance of nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome in the pathogenesis of cardiovascular diseases (CVDs), including hypertension, myocardial infarct (MI), ischemia, cardiomyopathies (CMs), heart failure (HF), and atherosclerosis. In this regard, intensive research efforts both in humans and in animal models of CVDs are being focused on the characterization of the pathophysiological role of NLRP3 inflammasome signaling in CVDs. In addition, clinical and preclinical evidence is coming to light that the pharmacological blockade of NLRP3 pathways with drugs, including novel chemical entities as well as drugs currently employed in the clinical practice, biologics and phytochemicals, could represent a suitable therapeutic approach for prevention and management of CVDs. On these bases, the present review article provides a comprehensive overview of clinical and preclinical studies about the role of NLRP3 inflammasome in the pathophysiology of CVDs, including hypertension, MI, ischemic injury, CMs, HF and atherosclerosis. In addition, particular attention has been focused on current evidence on the effects of drugs, biologics, and phytochemicals, targeting different steps of inflammasome signaling, in CVDs.
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Doenças Cardiovasculares , Inflamassomos , Animais , Doenças Cardiovasculares/tratamento farmacológico , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Compostos Fitoquímicos , Transdução de SinaisRESUMO
The present study was designed to examine the role of enteric glial cells (EGCs) in colonic neuromuscular dysfunctions in a mouse model of high-fat diet (HFD)-induced obesity. C57BL/6J mice were fed with HFD or standard diet (SD) for 1, 2, or 8 weeks. Colonic interleukin (IL)-1ß, IL-6, and malondialdehyde (MDA) levels were measured. Expression of occludin in colonic tissues was examined by western blot. Substance P (SP), S100ß, GFAP, and phosphorylated mitogen-activated protein kinase 1 (pERK) were assessed in whole mount specimens of colonic plexus by immunohistochemistry. Colonic tachykininergic contractions, elicited by electrical stimulation or exogenous SP, were recorded in the presence or absence of fluorocitrate (FC). To mimic exposure to HFD, cultured EGCs were incubated with palmitate (PA) and/or lipopolysaccharide (LPS). SP and IL-1ß levels were assayed in the culture medium by ELISA. HFD mice displayed an increase in colonic IL-1ß and MDA, and a reduction of occludin at week 2. These changes occurred to a greater extent at week 8. In vitro electrically evoked tachykininergic contractions were enhanced in HFD mice after 2 or 8 weeks, and they were blunted by FC. Colonic IL-6 levels as well as substance P and S100ß density in myenteric ganglia of HFD mice were increased at week 8, but not at week 1 or 2. In cultured EGCs, co-incubation with palmitate plus LPS led to a significant increase in both SP and IL-1ß release. HFD-induced obesity is characterized by a hyperactivation of EGCs and is involved in the development of enteric motor disorders through an increase in tachykininergic activity and release of pro-inflammatory mediators.
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Doenças do Colo/patologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Sistema Nervoso Entérico/patologia , Motilidade Gastrointestinal , Neuroglia/patologia , Obesidade/complicações , Animais , Doenças do Colo/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Adenosine, deriving from ATP released by dying cancer cells and then degradated in the tumor environment by CD39/CD73 enzyme axis, is linked to the generation of an immunosuppressed niche favoring the onset of neoplasia. Signals delivered by extracellular adenosine are detected and transduced by G-protein-coupled cell surface receptors, classified into four subtypes: A1, A2A, A2B, and A3. A critical role of this nucleoside is emerging in the modulation of several immune and nonimmune cells defining the tumor microenvironment, providing novel insights about the development of novel therapeutic strategies aimed at undermining the immune-privileged sites where cancer cells grow and proliferate.
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Adenosina/metabolismo , Neoplasias/metabolismo , Transdução de Sinais , Microambiente Tumoral , 5'-Nucleotidase/genética , Humanos , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Eye tracking techniques based on deep learning are rapidly spreading in a wide variety of application fields. With this study, we want to exploit the potentiality of eye tracking techniques in ocular proton therapy (OPT) applications. We implemented a fully automatic approach based on two-stage convolutional neural networks (CNNs): the first stage roughly identifies the eye position and the second one performs a fine iris and pupil detection. We selected 707 video frames recorded during clinical operations during OPT treatments performed at our institute. 650 frames were used for training and 57 for a blind test. The estimations of iris and pupil were evaluated against the manual labelled contours delineated by a clinical operator. For iris and pupil predictions, Dice coefficient (median = 0.94 and 0.97), Szymkiewicz-Simpson coefficient (median = 0.97 and 0.98), Intersection over Union coefficient (median = 0.88 and 0.94) and Hausdorff distance (median = 11.6 and 5.0 (pixels)) were quantified. Iris and pupil regions were found to be comparable to the manually labelled ground truths. Our proposed framework could provide an automatic approach to quantitatively evaluating pupil and iris misalignments, and it could be used as an additional support tool for clinical activity, without impacting in any way with the consolidated routine.
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Terapia com Prótons , Processamento de Imagem Assistida por Computador , Iris , Redes Neurais de Computação , PupilaRESUMO
Acadesine (ACA), a pharmacological activator of AMP-activated protein kinase (AMPK), showed a promising beneficial effect in a mouse model of colitis, indicating this drug as an alternative tool to manage IBDs. However, ACA displays some pharmacodynamic limitations precluding its therapeutical applications. Our study was aimed at evaluating the in vitro and in vivo effects of FA-5 (a novel direct AMPK activator synthesized in our laboratories) in an experimental model of colitis in rats. A set of experiments evaluated the ability of FA5 to activate AMPK and to compare the efficacy of FA5 with ACA in an experimental model of colitis. The effects of FA-5, ACA, or dexamethasone were tested in rats with 2,4-dinitrobenzenesulfonic acid (DNBS)-induced colitis to assess systemic and tissue inflammatory parameters. In in vitro experiments, FA5 induced phosphorylation, and thus the activation, of AMPK, contextually to the activation of SIRT-1. In vivo, FA5 counteracted the increase in spleen weight, improved the colon length, ameliorated macroscopic damage score, and reduced TNF and MDA tissue levels in DNBS-treated rats. Of note, FA-5 displayed an increased anti-inflammatory efficacy as compared with ACA. The novel AMPK activator FA-5 displays an improved anti-inflammatory efficacy representing a promising pharmacological tool against bowel inflammation.
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Proteínas Quinases Ativadas por AMP/metabolismo , Benzofuranos/uso terapêutico , Desenvolvimento de Medicamentos , Ativadores de Enzimas/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Animais , Benzofuranos/farmacologia , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Colo/efeitos dos fármacos , Colo/patologia , Dinitrofluorbenzeno/análogos & derivados , Eletroforese em Gel Bidimensional , Ontologia Genética , Doenças Inflamatórias Intestinais/patologia , Interleucina-10/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Baço/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND AND AIM: Patients with Parkinson's disease (PD) are often characterized by functional gastrointestinal disorders. Such disturbances can occur at all stages of PD and precede the typical motor symptoms of the disease by many years. However, the morphological alterations associated with intestinal disturbances in PD are undetermined. This study examined the remodelling of colonic wall in 6-hydroxydopamine (6-OHDA)-induced PD rats. METHODS: 8 weeks after 6-OHDA injection animals were sacrificed. Inflammatory infiltrates, collagen deposition and remodelling of intestinal epithelial barrier and tunica muscularis in the colonic wall were assessed by histochemistry, immunohistochemistry, immunofluorescence and western blot analysis. RESULTS: 6-OHDA rats displayed significant alterations of colonic tissues as compared with controls. Signs of mild inflammation (eosinophil infiltration) and a transmural deposition of collagen fibres were observed. Superficial colonic layers were characterized by severe morphological alterations. In particular, lining epithelial cells displayed a reduced claudin-1 and transmembrane 16A/Anoctamin 1 (TMEM16A/ANO1) expression; goblet cells increased their mucin expression; colonic crypts were characterized by an increase in proliferating epithelial cells; the density of S100-positive glial cells and vimentin-positive fibroblast-like cells was increased as well. Several changes were found in the tunica muscularis: downregulation of α-smooth muscle actin/desmin expression and increased proliferation of smooth muscle cells; increased vimentin expression and proliferative phenotype in myenteric ganglia; reduction of interstitial cells of Cajal (ICCs) density. CONCLUSIONS: A pathological remodelling occurs in the colon of 6-OHDA rats. The main changes include: enhanced fibrotic deposition; alterations of the epithelial barrier; activation of mucosal defense; reduction of ICCs. These results indicate that central nigrostriatal denervation is associated with histological changes in the large bowel at mucosal, submucosal and muscular level. These alterations might represent morphological correlates of digestive symptoms in PD.
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Colo/patologia , Neurônios Dopaminérgicos/patologia , Animais , Anoctamina-1 , Colo/metabolismo , Dopamina/metabolismo , Fibrose , Gastroenteropatias/metabolismo , Motilidade Gastrointestinal , Masculino , Oxidopamina , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Ratos , Ratos Sprague-Dawley , Substância NegraRESUMO
AIMS: Vedolizumab (VDZ) prevents migration of activated leucocytes into inflamed mucosa. This study aimed to assess the patterns of serum cytokines in ulcerative colitis (UC) patients at baseline and during VDZ treatment, and to investigate their association with mucosal healing and clinical remission. METHODS: We enrolled consecutive UC patients eligible for treatment with VDZ. A panel of serum cytokines were measured by fluorescence assay at weeks 0, 6 and 22. Colonoscopy was performed at baseline and week 54, to evaluate mucosal healing. The time trends of serum cytokines were analysed by log-linear mixed effect models, and their prognostic accuracy was evaluated by logistic regression. RESULTS: Out of 27 patients included in the analysis, at week 54 mucosal healing was achieved in 12 (44%) and clinical remission in 17 (63%). Mucosal healing was associated with higher interleukin (IL)-8 values at baseline and with significant decrease in IL-6 and IL-8 levels over the first 6 weeks. A significant reduction of IL-6 and IL-8 levels over the first 6 weeks of treatment was associated also with clinical remission. Logistic models including, among the predictors, IL-6 and IL-8 at baseline and their changes over the first 6 weeks of treatment had 83% sensitivity and 87% specificity to predict mucosal healing, and 82% sensitivity and 90% specificity to predict clinical remission. CONCLUSION: In UC patients, the serum patterns of IL-6 and IL-8 at baseline and over the first 6 weeks of treatment with VDZ could be useful to predict therapeutic outcome.
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Colite Ulcerativa , Anticorpos Monoclonais Humanizados , Citocinas , Humanos , Mucosa Intestinal , Resultado do TratamentoRESUMO
Over recent years, several investigations have suggested that Parkinson's disease (PD) can be regarded as the consequence of a bowel disorder. Indeed, gastrointestinal symptoms can occur at all stages of this neurodegenerative disease and in up to a third of cases, their onset can precede the involvement of the central nervous system. Recent data suggest that enteric glial cells (EGCs) may play a major role in PD-related gastrointestinal disturbances, as well as in the development and progression of the central disease. In addition to their trophic and structural functions, EGCs are crucial for the homeostatic control of a wide range of gastrointestinal activities. The main purpose of this review was to provide a detailed overview of the role of EGCs in intestinal PD-associated alterations, with particular regard for their participation in digestive and central inflammation as well as the dynamic interactions between glial cells and intestinal epithelial barrier. Accumulating evidence suggests that several pathological intestinal conditions, associated with an impairment of barrier permeability, may trigger dysfunctions of EGCs and their shift towards a proinflammatory phenotype. The reactive gliosis is likely responsible for PD-related neuroinflammation and the associated pathological changes in the ENS. Thus, ameliorating the efficiency of mucosal barrier, as well as avoiding IEB disruption and the related reactive gliosis, might theoretically prevent the onset of PD or, at least, counteract its progression.
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Sistema Nervoso Entérico/imunologia , Sistema Nervoso Entérico/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Neuroglia/imunologia , Neuroglia/metabolismo , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Transdução de Sinais , Animais , Encéfalo/metabolismo , Microbioma Gastrointestinal/imunologia , Humanos , alfa-Sinucleína/metabolismoRESUMO
Adenosine is a purine nucleoside, resulting from the degradation of adenosine triphosphate (ATP). Under adverse conditions, including hypoxia, ischemia, inflammation, or cancer, the extracellular levels of adenosine increase significantly. Once released, adenosine activates cellular signaling pathways through the engagement of the four known G-protein-coupled receptors, adenosine A1 receptor subtype (A1), A2A, A2B, and A3. These receptors, expressed virtually on all immune cells, mitigate all aspects of immune/inflammatory responses. These immunosuppressive effects contribute to blunt the exuberant inflammatory responses, shielding cells, and tissues from an excessive immune response and immune-mediated damage. However, a prolonged persistence of increased adenosine concentrations can be deleterious, participating in the creation of an immunosuppressed niche, ideal for neoplasia onset and development. Based on this evidence, the present review has been conceived to provide a comprehensive and critical overview of the involvement of adenosine system in shaping the molecular mechanisms underlying the enteric chronic inflammation and in promoting the generation of an immunosuppressive niche useful for the colorectal tumorigenesis.
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Adenosina/metabolismo , Neoplasias Associadas a Colite/metabolismo , Neoplasias Colorretais/metabolismo , Sistema Imunitário , Inflamação/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Receptores Purinérgicos P1/metabolismo , Animais , Neoplasias Associadas a Colite/imunologia , Neoplasias Associadas a Colite/patologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Sulfato de Dextrana/toxicidade , Humanos , Sistema Imunitário/citologia , Inflamação/imunologia , Doenças Inflamatórias Intestinais/imunologia , Transdução de Sinais/genéticaRESUMO
Increasing evidence suggests that intestinal dysfunctions may represent early events in Alzheimer's disease and contribute to brain pathology. This study examined the relationship between onset of cognitive impairment and colonic dysfunctions in a spontaneous AD model before the full development of brain pathology. SAMP8 mice underwent Morris water maze and assessment of faecal output at four, six and eight months of age. In vitro colonic motility was examined. Faecal and colonic Aß, tau proteins, α-synuclein and IL-1ß were assessed by ELISA. Colonic citrate synthase activity was assessed by spectrophotometry. Colonic NLRP3, caspase-1 and ASC expression were evaluated by Western blotting. Colonic eosinophil density and claudin-1 expression were evaluated by immunohistochemistry. The effect of Aß on NLRP3 signalling and mitochondrial function was tested in cultured cells. Cognitive impairment and decreased faecal output occurred in SAMP8 mice from six months. When compared with SAMR1, SAMP8 animals displayed: (1) impaired in vitro colonic contractions; (2) increased enteric AD-related proteins, IL-1ß, active-caspase-1 expression and eosinophil density; and (3) decreased citrate synthase activity and claudin-1 expression. In THP-1 cells, Aß promoted IL-1ß release, which was abrogated upon incubation with caspase-1 inhibitor or in ASC-/- cells. Aß decreased mitochondrial function in THP-1 cells. In SAMP8, enteric AD-related proteins deposition, inflammation and impaired colonic excitatory neurotransmission, occurring before the full brain pathology development, could contribute to bowel dysmotility and represent prodromal events in AD.