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1.
J Sleep Res ; : e14257, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38888109

RESUMO

Sleep problems are associated with increased risk of obesity. Multiple mechanisms have been identified to support this relationship, including changes in sensory processing and food choice. Taste researchers have recently begun to explore whether changes in taste occur as a result of short-term or long-term sleep habits. A systematic review was conducted to investigate these relationships. A total of 13 studies were included in the review. Heterogeneity in both the sleep and taste measurements used was noted, and most studies failed to assess sour, bitter and umami tastes. Still, the available evidence suggests that sweet taste hedonic perception appears to be undesirably influenced by short sleep when viewed through the lens of health. That is, preferred sweetness concentration increases as sleep duration decreases. Habitual sleep and interventions curtailing sleep had minimal associations or effects on sweet taste sensitivity. Salt taste sensitivity and hedonic responses appear to be relatively unaffected by insufficient sleep, but more work is needed. Solid evidence on other taste qualities is not available at the present time.

2.
Crit Rev Food Sci Nutr ; 63(16): 2613-2625, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-34904473

RESUMO

Diet therapy for diabetes involves controlling carbohydrate intake in order to manage blood glucose concentrations. Simple carbohydrates, like sucrose, quickly and potently raise blood glucose when ingested, and are typically perceived as sweet. Sweetness is innately pleasurable and contributes to the positive hedonic evaluation of foods and beverages. There is some evidence to suggest that individuals with diabetes mellitus may be less able to detect sweetness, which could result in increased intake and, thus, more difficulty managing blood glucose. A systematic review that included PubMed, PsycInfo, and Embase databases was conducted. Inclusion criteria included observational studies that investigated the sweet taste function of adults with and without diabetes mellitus (Prospero CRD42021225058). The quality of the final included studies was assessed using the Academy of Nutrition and Dietetics' Evidence Analysis Library Quality Criteria Checklist: Primary Research tool. Eighteen studies that compared sweet taste thresholds, intensity ratings, or hedonic responses in adults both with and without diabetes were included. Differences in sweet taste thresholds, both detection and recognition, indicated that individuals with diabetes were less sensitive than healthy controls. The same findings were observed for intensity ratings. Only two studies examined hedonic responses; results were inconclusive.


Assuntos
Diabetes Mellitus , Paladar , Adulto , Humanos , Paladar/fisiologia , Glicemia , Preferências Alimentares , Percepção Gustatória/fisiologia , Sacarose
3.
Behav Sleep Med ; 21(5): 601-607, 2023 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-36377788

RESUMO

OBJECTIVE: Community-delivered sleep education interventions have been demonstrated to be effective in improving sleep outcomes, but whether these benefits persist once the program ends is not well characterized. This study sought to determine whether the previously reported positive effects attributed to the SLeep Education for Elders Program (SLEEP) were maintained six months after program completion. METHOD: Nineteen participants were surveyed three times: at baseline, program completion (six weeks), and the six-month post-program timepoint. Sleep outcomes for quality, duration, insomnia symptoms, sleep hygiene behaviors, and excessive daytime sleepiness were assessed using validated surveys, including the Pittsburgh Sleep Quality Index (from which duration was also extracted), the Insomnia Severity Index, the Sleep Hygiene Index, and the Epworth Sleepiness Scale. RESULTS: Longitudinal models adjusted for baseline sleep problems revealed the benefits achieved immediately after the program were retained at six months for sleep quality (estimate: -2.0 (95%CI: -2.7, -1.3)), sleep duration (estimate: 0.9 (95%CI: 0.6, 1.2)), insomnia symptoms (estimate: -3.5 95%CI: (-4.6, -2.3)), and sleep hygiene behaviors (estimate: -2.6 (-4.3, -0.9)). CONCLUSIONS: These results suggest that a community-delivered sleep education intervention can produce sustained benefits for participants and should be considered as a tool to address uncomplicated sleep issues.


Assuntos
Distúrbios do Sono por Sonolência Excessiva , Distúrbios do Início e da Manutenção do Sono , Humanos , Idoso , Distúrbios do Início e da Manutenção do Sono/terapia , Sono , Inquéritos e Questionários , Higiene do Sono
4.
Adv Physiol Educ ; 47(2): 194-201, 2023 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-36759146

RESUMO

Ripple Effects Mapping (REM) is a qualitative data analysis approach that combines mind mapping with inductive analysis to condense data obtained from group interviews. One benefit of REM is the ability to identify unintended outcomes, or "ripples," of the intervention of interest. Ripples are visually represented by a mind map created during the REM session. Mind maps connect related concepts, typically with the main concept in the center of the map and supporting ideas radiating from a central node. This project applied REM to undergraduate course evaluation. The purpose of this study was threefold: to use REM to identify undergraduate student-perceived benefits of research projects, to assess whether REM could be used to confirm achievement of course learning objectives, and to compare the themes identified from the mind mapping component of REM to those identified by inductive analysis. Mind maps were generated with Xmind (Xmind Ltd., Hong Kong) during online sessions by two groups of students, those who completed a "mandatory" research project (n = 11) and those who chose to participate in an additional "optional" research project (n = 9). There was considerable overlap in identified themes between mind mapping and inductive analysis, with skills, relationships, career direction, and unexpected benefits identified by both techniques. Mind mapping identified several additional themes. Findings from both approaches were compared to course learning objectives, and both confirmed that all objectives were met. In situations where time is a limiting factor, mind mapping could be superior to the complete REM approach for course learning objective assessments.NEW & NOTEWORTHY This study used Ripple Effects Mapping (REM) to identify undergraduate student-perceived benefits of research projects, to assess whether REM could confirm achievement of course learning objectives for a research project-based course, and to compare themes identified from the mind mapping component of REM to those identified by inductive analysis. Mind mapping confirmed achievement of course objectives and may be a better choice compared to inductive reasoning when time is limited.


Assuntos
Educação de Graduação em Medicina , Aprendizagem , Humanos , Estudantes , Resolução de Problemas
5.
Int J Mol Sci ; 24(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36614194

RESUMO

Survival from pancreatic cancer is poor because most cancers are diagnosed in the late stages and there are no therapies to prevent the progression of precancerous pancreatic intraepithelial neoplasms (PanINs). Inhibiting mutant KRASG12D, the primary driver mutation in most human pancreatic cancers, has been challenging. The cholecystokinin-B receptor (CCK-BR) is absent in the normal pancreas but becomes expressed in high grade PanIN lesions and is over-expressed in pancreatic cancer making it a prime target for therapy. We developed a biodegradable nanoparticle polyplex (NP) that binds selectively to the CCK-BR on PanINs and pancreatic cancer to deliver gene therapy. PanIN progression was halted and the pancreas extracellular matrix rendered less carcinogenic in P48-Cre/LSL-KrasG12D/+ mice treated with the CCK-BR targeted NP loaded with siRNA to mutant Kras. The targeted NP also slowed proliferation, decreased metastases and improved survival in mice bearing large orthotopic pancreatic tumors. Safety and toxicity studies were performed in immune competent mice after short or long-term exposure and showed no off-target toxicity by histological or biochemical evaluation. Precision therapy with target-specific NPs provides a novel approach to slow progression of advanced pancreatic cancer and also prevents the development of pancreatic cancer in high-risk subjects without toxicity to other tissues.


Assuntos
Carcinoma in Situ , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Camundongos , Humanos , Animais , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Modelos Animais de Doenças , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/prevenção & controle , Pâncreas/metabolismo , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma in Situ/genética , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas
6.
Br J Cancer ; 126(5): 754-763, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34876673

RESUMO

BACKGROUND: Thymic epithelial tumours (TETs) are rare tumours comprised of thymomas and thymic carcinoma. Novel therapies are needed, especially in thymic carcinoma where the 5-year survival rate hovers at 30%. Mesothelin (MSLN), a surface glycoprotein that is cleaved to produce mature MSLN (mMSLN) and megakaryocyte potentiating factor (MPF), is expressed in limited tissues. However, its expression is present in various cancers, including thymic carcinoma, where it is expressed in 79% of cases. METHODS: We utilised flow cytometry, in vitro cytotoxicity assays, and an in vivo xenograft model in order to demonstrate the ability of the MSLN targeting antibody-drug conjugate (ADC) anetumab ravtansine (ARav) in inhibiting the growth of thymic carcinoma. RESULTS: Thymoma and thymic carcinoma cell lines express MSLN, and anetumab, the antibody moiety of ARav, was capable of binding MSLN expressing thymic carcinoma cells and internalising. ARav was effective at inhibiting the growth of thymic carcinoma cells stably transfected with mMSLN in vitro. In vivo, 15 mg/kg ARav inhibited T1889 xenograft tumour growth, while combining 7.5 mg/kg ARav with 4 mg/kg cisplatin yielded an additive effect on inhibiting tumour growth. CONCLUSIONS: These data demonstrate that anetumab ravtansine inhibits the growth of MSLN positive thymic carcinoma cells in vitro and in vivo.


Assuntos
Imunoconjugados/administração & dosagem , Maitansina/análogos & derivados , Mesotelina/genética , Mesotelina/metabolismo , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Timoma/tratamento farmacológico , Neoplasias do Timo/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/administração & dosagem , Cisplatino/farmacologia , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HT29 , Humanos , Imunoconjugados/farmacologia , Maitansina/administração & dosagem , Maitansina/farmacologia , Camundongos , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/metabolismo , Timoma/genética , Timoma/metabolismo , Neoplasias do Timo/genética , Neoplasias do Timo/metabolismo , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Sleep Res ; 31(5): e13551, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35137471

RESUMO

Media use has been linked to sleep disturbance, but the results are inconsistent. This study explores moderating conditions. A media diary study with 58 free-living adults measured the time spent with media before bed, the location of use, and multitasking. Electroencephalography (EEG) captured bedtime, total sleep time, and the percent of time spent in deep (Stage N3), and rapid eye movement (REM) sleep. Media use in the hour before sleep onset was associated with an earlier bedtime. If the before bed use did not involve multitasking and was conducted in bed, that use was also associated with more total sleep time. Media use duration was positively associated with (later) bedtime and negatively associated with total sleep time. Sleep quality, operationalised as the percent of total sleep time spent in N3 and REM sleep, was unaffected by media use before bed. Bedtime media use might not be as detrimental for sleep as some previous research has shown. Important contextual variables moderate the relationship, such as location, multitasking, and session length.


Assuntos
Eletroencefalografia , Sono , Adulto , Humanos , Polissonografia , Sono REM
8.
Adv Physiol Educ ; 46(4): 742-751, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36302137

RESUMO

The COVID-19 pandemic led to the suspension of in-person learning at many higher education institutions (HEIs) in March 2020. In response, HEIs transitioned most courses to online formats immediately and continued this mode of instruction through the 2020-2021 academic year. In fall 2021, numerous HEIs resumed in-person courses and some hybrid courses, and faculty began noting academic-related behavior deficiencies not previously observed in students. Focus groups of teaching faculty (n = 8) from one university department were conducted to gather information on changes in student academic-related behaviors attributed to the disruption of teaching and learning due to COVID-19 and to compare observed deficiencies with the university's undergraduate learning goals. Mind mapping software was utilized to capture themes and subthemes. Identified themes were related to problem-solving skills, grades, time management, attendance, and interpersonal communication, both in terms of student-to-student and student-to-faculty communication. For these identified areas, outcomes during the return to in-person learning were mostly undesirable. Based on these identified issues, suggested modifications that HEIs could use to modify course content and delivery to offset skill gaps and improve interpersonal communication were identified. Furthermore, observations may indicate that fully remote learning inhibited student learning and skill development during the 2020-2021 academic year. Future work should examine the effectiveness of the proposed modifications on student success.NEW & NOTEWORTHY This article contains information gathered from mind map-driven faculty focus group observations of student academic-related deficiencies resulting from transitioning from remote to in-person learning and how said deficiencies compare to university undergraduate learning goals.


Assuntos
COVID-19 , Humanos , Pandemias , Aprendizagem , Estudantes , Docentes
9.
Int J Mol Sci ; 23(3)2022 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-35163821

RESUMO

Nonalcoholic steatohepatitis (NASH) is associated with obesity, metabolic syndrome, and dysbiosis of the gut microbiome. Cholecystokinin (CCK) is released by saturated fats and plays an important role in bile acid secretion. CCK receptors are expressed on cholangiocytes, and CCK-B receptor expression increases in the livers of mice with NASH. The farnesoid X receptor (FXR) is involved in bile acid transport and is a target for novel therapeutics for NASH. The aim of this study was to examine the role of proglumide, a CCK receptor inhibitor, in a murine model of NASH and its interaction at FXR. Mice were fed a choline deficient ethionine (CDE) diet to induce NASH. Some CDE-fed mice received proglumide-treated drinking water. Blood was collected and liver tissues were examined histologically. Proglumide's interaction at FXR was evaluated by computer modeling, a luciferase reporter assay, and tissue FXR expression. Stool microbiome was analyzed by RNA-Sequencing. CDE-fed mice developed NASH and the effect was prevented by proglumide. Computer modeling demonstrated specific binding of proglumide to FXR. Proglumide binding in the reporter assay was consistent with a partial agonist at the FXR with a mean binding affinity of 215 nM. FXR expression was significantly decreased in livers of CDE-fed mice compared to control livers, and proglumide restored FXR expression to normal levels. Proglumide therapy altered the microbiome signature by increasing beneficial and decreasing harmful bacteria. These data highlight the potential novel mechanisms by which proglumide therapy may improve NASH through interaction with the FXR and consequent alteration of the gut microbiome.


Assuntos
Bactérias/classificação , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Proglumida/administração & dosagem , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Bactérias/genética , Bactérias/isolamento & purificação , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/metabolismo , Filogenia , Proglumida/química , Proglumida/farmacologia , Receptores Citoplasmáticos e Nucleares/química
10.
Dig Dis Sci ; 65(5): 1376-1384, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31598921

RESUMO

BACKGROUND AND AIMS: Chronic pancreatitis is associated with recurrent inflammation, pain, fibrosis, and loss of exocrine and endocrine pancreatic function and risk of cancer. We hypothesized that activation of the CCK receptor contributes to pancreatitis and blockade of this pathway would improve chronic pancreatitis. METHODS: Two murine models were used to determine whether CCK receptor blockade with proglumide could prevent and reverse histologic and biochemical features of chronic pancreatitis: the 6-week repetitive chronic cerulein injection model and the modified 75% choline-deficient ethionine (CDE) diet. In the CDE-fed model, half the mice received water supplemented with proglumide, for 18 weeks. After chronic pancreatitis was established in the cerulein model, half the mice were treated with proglumide and half with water. Histology was scored in a blinded fashion for inflammation, fibrosis and acinar ductal metaplasia (ADM) and serum lipase levels were measured. RNA was extracted and examined for differentially expressed fibrosis genes. RESULTS: Proglumide therapy decreased pancreatic weight in the CDE diet study and the cerulein-induced chronic pancreatitis model. Fibrosis, inflammation, and ADM scores were significantly reduced in both models. Lipase values improved with proglumide but not in controls in both models. Proglumide decreased pancreas mRNA expression of amylase, collagen-4, and TGFßR2 gene expression by 44, 38, and 25%, respectively, compared to control mice. CONCLUSION: New strategies are needed to decreased inflammation and reduce fibrosis in chronic pancreatitis. CCK receptor antagonist therapy may improve chronic pancreatitis by reversing fibrosis and inflammation. The decrease in ADM may reduce the risk of the development of pancreatic cancer.


Assuntos
Pâncreas/patologia , Pancreatite Crônica/tratamento farmacológico , Proglumida/farmacologia , Receptores da Colecistocinina/agonistas , Animais , Ceruletídeo , Doença Crônica , Modelos Animais de Doenças , Fibrose , Inflamação , Lipase/sangue , Camundongos , Pancreatite Crônica/induzido quimicamente , Pancreatite Crônica/patologia
11.
Dig Dis Sci ; 65(1): 189-203, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31297627

RESUMO

BACKGROUND AND AIMS: Nonalcoholic steatohepatitis (NASH) is a common inflammatory liver condition that may lead to cirrhosis and hepatocellular carcinoma (HCC). Risk factors for NASH include a saturated fat diet, altered lipid metabolism, and genetic and epigenetic factors, including microRNAs. Serum levels of cholecystokinin (CCK) are elevated in mice and humans that consume a high-saturated fat diet. CCK receptors (CCK-Rs) have been reported on fibroblasts which when activated can induce fibrosis; however, their role in hepatic fibrosis remains unknown. We hypothesized that elevated levels of CCK acting on the CCK-Rs play a role in the development of NASH and in NASH-associated HCC. METHODS: We performed a NASH Prevention study and Reversal study in mice fed a saturated fat 75% choline-deficient-ethionine-supplemented (CDE) diet for 12 or 18 weeks. In each study, half of the mice received untreated drinking water, while the other half received water supplemented with the CCK-R antagonist proglumide. CCK-R expression was evaluated in mouse liver and murine HCC cells. RESULTS: CCK receptor antagonist treatment not only prevented NASH but also reversed hepatic inflammation, fibrosis, and steatosis and normalized hepatic transaminases after NASH was established. Thirty-five percent of the mice on the CDE diet developed HCC compared with none in the proglumide-treated group. We found that CCK-BR expression was markedly upregulated in mouse CDE liver and HCC cells compared with normal hepatic parenchymal cells, and this expression was epigenetically regulated by microRNA-148a. CONCLUSION: These results support the novel role of CCK receptors in the pathogenesis of NASH and HCC.


Assuntos
Carcinoma Hepatocelular/prevenção & controle , Antagonistas de Hormônios/farmacologia , Neoplasias Hepáticas/prevenção & controle , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Proglumida/farmacologia , Receptor de Colecistocinina B/antagonistas & inibidores , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Deficiência de Colina/complicações , Modelos Animais de Doenças , Epigênese Genética , Etionina , Feminino , Regulação Neoplásica da Expressão Gênica , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Receptor de Colecistocinina B/genética , Receptor de Colecistocinina B/metabolismo , Transdução de Sinais
12.
Am J Physiol Gastrointest Liver Physiol ; 317(5): G682-G693, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31433212

RESUMO

Growth of pancreatic cancer is stimulated by gastrin in both a paracrine and an autocrine fashion. Traditional therapies have not significantly improved survival, and recently pancreatic cancer has been deemed a "cold" tumor due to its poor response to immunotherapy. Strategies to improve survival of pancreatic cancer are desperately needed. In the current investigation, we studied the effects of an anti-gastrin cancer vaccine, polyclonal antibody stimulator (PAS; formerly called G17DT and Gastrimmune), used alone or in combination with a programmed cell death receptor (PD)-1 immune checkpoint antibody on pancreatic cancer growth, metastases, and the tumor microenvironment (TME). Immune-competent female C57BL/6 mice bearing syngeneic orthotopic murine pancreatic cancer treated with PAS had significantly smaller tumors and fewer metastases. Examination of the TME demonstrated decreased fibrosis with fewer M2 and more M1 tumor-associated macrophages. Expression of the E-cadherin gene was significantly increased and expression of the TGFßR2 gene was decreased compared with controls. Mice treated with PAS or the combination of PAS and PD-1 antibody exhibited significantly less tumor expression of phospho-paxillin, the focal adhesion protein ß-catenin, and matrix metalloproteinase-7. This study suggests that inhibition of the cancer-promoting effects of gastrin in pancreatic cancer can decrease metastases by altering the TME and decreasing pathways that activate the epithelial mesenchymal transition. The PAS vaccine appears to change the TME, making it more susceptible to therapy with an immune checkpoint antibody. This novel combination of two immunotherapies may improve survival of pancreatic cancer by decreasing both tumor growth and metastasis formation.NEW & NOTEWORTHY Survival from advanced pancreatic cancer is poor, in part due to dense fibrosis of the tumor microenvironment, increased number of M2-polarized macrophages that promote angiogenesis and invasion, and lack of "target-specific" therapy. Herein, we report that a tumor vaccine that selectively targets gastrin decreases pancreatic cancer growth and metastases. Furthermore, the gastrin vaccine polyclonal antibody stimulator alters the tumor microenvironment rendering it more responsive to immunotherapy with a programmed cell death receptor-1 immune checkpoint antibody.


Assuntos
Vacinas Anticâncer/imunologia , Gastrinas/imunologia , Imunoterapia/métodos , Neoplasias Pancreáticas/terapia , Animais , Caderinas/genética , Caderinas/metabolismo , Vacinas Anticâncer/uso terapêutico , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Gastrinas/uso terapêutico , Macrófagos/metabolismo , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 7 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Neoplasias Pancreáticas/patologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Microambiente Tumoral , beta Catenina/genética , beta Catenina/metabolismo
13.
Am J Physiol Gastrointest Liver Physiol ; 315(5): G699-G712, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29927319

RESUMO

The gastrointestinal peptide cholecystokinin (CCK) is released from the duodenum in response to dietary fat to aid in digestion, and plasma CCK levels are elevated with the consumption of high-fat diets. CCK is also a trophic peptide for the pancreas and has also been shown to stimulate growth of pancreatic cancer. In the current investigation, we studied the influence of a diet high in saturated fat on the growth of pancreatic cancer in syngeneic murine models before the mice became obese to exclude the confounding factors associated with obesity. The high-fat diet significantly increased growth and metastasis of pancreatic cancer compared with the control diet, and the stimulatory effect was blocked by the CCK-receptor antagonist proglumide. We then selectively knocked out the CCK receptor on the pancreatic cancer cells using clustered regularly interspaced short palindromic repeats technology and showed that without CCK-receptors, dietary fat was unable to stimulate cancer growth. We next demonstrated that dietary fat failed to influence pancreatic cancer xenograft growth in genetically engineered CCK peptide knockout mice. The tumor-associated fibrosis that is so prevalent in the pancreatic cancer microenvironment was significantly decreased with CCK-receptor antagonist therapy because fibroblasts also have CCK receptors. The CCK-receptor antagonist proglumide also altered tumor metalloprotease expression and increased tumor suppressor genes by a PCR array. Our studies confirm that a diet high in saturated fat promotes growth of pancreatic cancer and the action is mediated by the CCK-receptor pathway. NEW & NOTEWORTHY Diets high in long-chain saturated fats promote growth of pancreatic cancer independent of obesity. The mechanism through which dietary fat promotes cancer is mediated through the cholecystokinin (CCK) receptor pathway. Therapy with a CCK-receptor antagonist altered the tumor microenvironment by reducing fibrosis, increasing cluster of differentiation 8+ lymphocytes, increasing tumor suppressor genes, and thus decreasing metastases. Use of CCK-receptor antagonist therapy with standard chemotherapy for pancreatic cancer may improve response by altering the tumor microenvironment.


Assuntos
Gorduras na Dieta/efeitos adversos , Neoplasias Pancreáticas/etiologia , Receptores da Colecistocinina/metabolismo , Microambiente Tumoral , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Feminino , Fibrose , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/tratamento farmacológico , Proglumida/farmacologia , Proglumida/uso terapêutico , Receptores da Colecistocinina/antagonistas & inibidores , Receptores da Colecistocinina/genética
14.
Chem Senses ; 43(4): 223-228, 2018 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-29522075

RESUMO

Little is known about the relationship between sleep and chemosensation. The purpose of this study was to characterize the relationship between chemosensory function and sleep duration, quality, and architecture. A total of 56 nonobese (body mass index <30 kg/m2) female participants who denied having diagnosed sleep disorders completed testing. Sleep was measured for two nights using a single-channel (A1-A2) electroencephalogram (Zmachine). Sweet taste threshold and preference as well as olfactory threshold, recognition ability, and pleasantness ratings were evaluated. Sweet taste preference was correlated with total sleep time (TST) (P = 0.0074) as well as with the sum of rapid eye movement (REM) and stage N3/slow wave sleep (SWS) duration (P = 0.0008). Participants who slept more than the average TST or more than the average REM + SWS time preferred lower concentrations of sweetness (P = 0.041 and 0.049, respectively), than those whose sleep times fell below the means. Multiple linear regression revealed that REM and SWS predicted ~18% of the variance of sweet taste preference. These findings suggest that scientific and consumer studies related to sweet preference might benefit from screening participants for short sleep duration prior to testing.


Assuntos
Percepção Olfatória/fisiologia , Sono/fisiologia , Limiar Gustativo/fisiologia , Adulto , Índice de Massa Corporal , Eletroencefalografia , Feminino , Humanos , Modelos Lineares , Sono REM , Sono de Ondas Lentas , Edulcorantes/química , Adulto Jovem
15.
Food Qual Prefer ; 65: 175-180, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31320785

RESUMO

Different patterns of sweet liking exist. For some, liking increases as concentration increases up to a point at which it typically plateaus. These individuals are referred to as sweet likers. How sweet likers' beverage intake, especially sugar sweetened beverage intake, differs from sweet dislikers' beverage intake is not well characterized. A total of 953 visitors (650 adults; 62.0% women; 303 children; 58.7% girls) to the Denver Museum of Nature & Science rated the taste intensity and liking of 5 sucrose solutions that spanned concentrations typically encountered in sugar-sweetened beverages (0.0-13.7% w/v) using visual analog scales. Beverage intake by adults was quantified using the validated BEVQ-15 questionnaire. Among adults, hierarchical cluster analysis identified three clusters of liking patterns (likers, dislikers, and neutrals). Among children, two clusters of liking patterns were identified (likers and dislikers). For both adults and children, BMI, percent body fat, age, and sex did not differ between clusters. Concentration by cluster interaction effects were observed for both adults and children. Adult sweet likers consumed more energy from all beverages, more sweetened juice and tea, and less water than those in other clusters. Sweet liker status may be a useful predictor of increased energy intake from beverages, but prospective trials are necessary to confirm this utility.

16.
Chem Senses ; 42(9): 769-775, 2017 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-28968903

RESUMO

Dietary fats serve multiple essential roles in human health but may also contribute to acute and chronic health complications. Thus, understanding mechanisms that influence fat ingestion are critical. All sensory systems may contribute relevant cues to fat detection, with the most recent evidence supporting a role for the sense of taste. Taste detection thresholds for fat vary markedly between individuals and responses are not normally distributed. Genetics may contribute to these observations. Using crowdsourced data obtained from families visiting the Denver Museum of Nature & Science, our objective was to estimate the heritability of fat taste (oleogustus). A pedigree analysis was conducted with 106 families (643 individuals) who rated the fat taste intensity of graded concentrations of linoleic acid (LA) embedded in taste strips. The findings estimate that 19% (P = 0.043) of the variability of taste response to LA relative to baseline is heritable at the highest concentration tested.


Assuntos
Ácido Linoleico/farmacologia , Paladar/efeitos dos fármacos , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Linhagem , Fatores Sexuais , Percepção Gustatória/efeitos dos fármacos , Percepção Gustatória/fisiologia , Adulto Jovem
17.
J Hepatol ; 63(2): 329-36, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25772035

RESUMO

BACKGROUND & AIMS: Current hepatitis B virus (HBV) management is challenging as treatment with nucleos(t)ide analogues needs to be maintained indefinitely and because interferon (IFN)-α therapy is associated with considerable toxicity. Previously, we showed that linking IFNα to apolipoprotein A-I generates a molecule (IA) with distinct antiviral and immunostimulatory activities which lacks the hematological toxicity of IFNα. METHODS: Here, we analyse the antiviral potential of an adeno-associated vector encoding IFNα fused to apolipoprotein A-I (AAV-IA) in comparison to a vector encoding only IFNα (AAV-IFN) in two animal models of chronic hepadnavirus infection. RESULTS: In HBV transgenic mice, we found that both vectors induced marked reductions in serum and liver HBV DNA and in hepatic HBV RNA but AAV-IFN caused lethal pancytopenia. Woodchucks with chronic hepatitis virus (WHV) infection that were treated by intrahepatic injection of vectors encoding the woodchuck sequences (AAV-wIFN or AAV-wIA), experienced only a slight reduction of viremia which was associated with hematological toxicity and high mortality when using AAV-wIFN, while AAV-wIA was well tolerated. However, when we tested AAV-wIA or a control vector encoding woodchuck apolipoprotein A-I (AAV-wApo) in combination with entecavir, we found that AAV-wApo-treated animals exhibited an immediate rebound of viral load upon entecavir withdrawal while, in AAV-wIA-treated woodchucks, viremia and antigenemia remained at low levels for several weeks following entecavir interruption. CONCLUSIONS: Treatment with AAV-IA is safe and elicits antiviral effects in animal models with difficult to treat chronic hepadnavirus infection. AAV-IA in combination with nucleos(t)ide analogues represents a promising approach for the treatment of HBV infection in highly viremic patients.


Assuntos
Apolipoproteína A-I/metabolismo , DNA Viral/genética , Terapia Genética/métodos , Hepadnaviridae/genética , Hepatite B Crônica/terapia , Interferon-alfa/uso terapêutico , Fígado/efeitos dos fármacos , Animais , Antivirais/uso terapêutico , Modelos Animais de Doenças , Feminino , Vetores Genéticos , Hepatite B Crônica/genética , Hepatite B Crônica/virologia , Fígado/virologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
18.
Chem Senses ; 40(8): 557-63, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26232811

RESUMO

Findings from studies examining interactions between fat taste and dietary fat intake or body weight are mixed. A convenience sample of 735 visitors to the Denver Museum of Nature & Science ≥8 years old rated the taste intensity of edible taste strips impregnated with varying concentrations (%v/v) of linoleic acid (LA) (blank = 0.0, low = 0.06, medium = 0.15, high = 0.38). Percent body fat (BF%) was measured using bioelectrical impedance. Fat taste intensity was rated as significantly different across all concentrations (P < 0.001) except between the blank and low concentrations (P = 0.1). Ratings increased monotonically across concentrations. Children (<18 years; N = 180) rated all concentrations as more intense than adults (P < 0.001 for all). Women and girls rated the highest concentration as more intense than men and boys (P < 0.02 for all). BF% was not correlated with fat taste intensity ratings. Self-reported dietary intake indicated that obese individuals' intensity ratings for medium and high concentrations of LA were inversely related to recent mono- and poly-unsaturated fat exposure (r = -0.19 to -0.27; P < 0.03 for all). No such associations were observed in the nonobese group. Findings suggest that factors other than simple adiposity status influence fat taste intensity ratings, and that participants in fat taste studies should receive standardized meals prior to testing.


Assuntos
Ácido Linoleico/química , Boca/fisiologia , Obesidade/fisiopatologia , Adolescente , Adulto , Fatores Etários , Criança , Feminino , Humanos , Ácido Linoleico/farmacologia , Masculino , Fatores Sexuais , Percepção Gustatória/efeitos dos fármacos , Limiar Gustativo/efeitos dos fármacos
19.
Chem Senses ; 39(4): 349-57, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24591531

RESUMO

The objective of this study was to examine the reliability of associations between fat taste, hunger, dietary fat intake, and body mass index (BMI). Detection thresholds for oleic acid (OA) were obtained during each of 7 consecutive visits using a modified staircase procedure. Participants were 48 (N = 17 male; N = 31 female) healthy adults (mean age: 28.5 ± 10.4 years) with BMI's ranging from 18.9 to 47.2 (≥ 25 kg · m(-2), N = 24). OA detection thresholds and self-reported hunger (100-mm visual analog scale) were assessed at each visit. BMI and dietary fat intake (Block Rapid Fat Screener) were determined at baseline. There was a significant decrease of threshold concentration over repeated trials among lean and overweight (BMI between 25.0 and 29.9 kg · m(-2)) participants but not in the obese. Combining the lean and overweight and contrasting their responses to the obese revealed the lean plus overweight group to be significantly more sensitive at visits 6 and 7. No change of threshold sensitivity or correlation with fat intake was observed in the obese participants unlike findings in the lean and lean plus overweight participants. Correlations between saturated fat intake and threshold sensitivity were positive (greater intake associated with higher thresholds) at baseline for the group, with additional correlations observed among the lean plus overweight but not in the obese, leaving open questions about the nutritional significance of the association. No significant associations were observed between sensitivity to OA and hunger. Repeated testing is required to assess associations between fat taste and other outcome variables.


Assuntos
Gorduras na Dieta , Paladar/fisiologia , Adulto , Índice de Massa Corporal , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Humanos , Masculino , Obesidade/psicologia , Ácido Oleico/farmacologia , Sobrepeso , Limiar Gustativo , Magreza
20.
Chem Senses ; 38(4): 325-32, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23377369

RESUMO

Findings that support the ability of humans to taste nonesterified fatty acids have been qualified by claims of substantial individual variability in sensitivity. We tested whether the number of testing visits impacted detection thresholds. Additionally, we explored the possibility that methodological differences in reported studies contributed to the high level of variance. Participants were randomized to either the modified staircase or ascending 3-alternative forced-choice methods, completed 10 test visits, and then switched to the alternate method. Repeated testing lowered the threshold concentration, and regardless of starting method, threshold concentrations were significantly lower with the second method. The staircase method generated data with less variation. The ascending method appears to be able to distinguish hypo and hypersensitive individuals as the variance at each visit increased over time, suggesting that the top performers continued to improve while the hyposensitive subjects maintained their low level of performance. The best individual threshold performance (lowest stimulus concentration) at each visit was obtained with the ascending method for 7 out of the first 10 visits (P = 0.117) and 17 out of the 20 visits (P = 0.001). Despite potential advantages of the ascending method in terms of sensitivity separation, there was no difference between the median of the first 10 visits, second 10 visits, and overall median obtained by the 2 testing methods. The most appropriate detection threshold testing method will depend on the goals of the researcher.


Assuntos
Ácidos Graxos não Esterificados/fisiologia , Limiar Gustativo , Adulto , Estudos Cross-Over , Feminino , Humanos , Masculino , Psicofísica/métodos , Adulto Jovem
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