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OBJECTIVE: To determine the risk of hospital admission with covid-19 and severe covid-19 among teachers and their household members, overall and compared with healthcare workers and adults of working age in the general population. DESIGN: Population based nested case-control study. SETTING: Scotland, March 2020 to July 2021, during defined periods of school closures and full openings in response to covid-19. PARTICIPANTS: All cases of covid-19 in adults aged 21 to 65 (n=132 420) and a random sample of controls matched on age, sex, and general practice (n=1 306 566). Adults were identified as actively teaching in a Scottish school by the General Teaching Council for Scotland, and their household members were identified through the unique property reference number. The comparator groups were adults identified as healthcare workers in Scotland, their household members, and the remaining general population of working age. MAIN OUTCOME MEASURES: The primary outcome was hospital admission with covid-19, defined as having a positive test result for SARS-CoV-2 during hospital admission, being admitted to hospital within 28 days of a positive test result, or receiving a diagnosis of covid-19 on discharge from hospital. Severe covid-19 was defined as being admitted to intensive care or dying within 28 days of a positive test result or assigned covid-19 as a cause of death. RESULTS: Most teachers were young (mean age 42), were women (80%), and had no comorbidities (84%). The risk (cumulative incidence) of hospital admission with covid-19 was <1% for all adults of working age in the general population. Over the study period, in conditional logistic regression models adjusted for age, sex, general practice, race/ethnicity, deprivation, number of comorbidities, and number of adults in the household, teachers showed a lower risk of hospital admission with covid-19 (rate ratio 0.77, 95% confidence interval 0.64 to 0.92) and of severe covid-19 (0.56, 0.33 to 0.97) than the general population. In the first period when schools in Scotland reopened, in autumn 2020, the rate ratio for hospital admission in teachers was 1.20 (0.89 to 1.61) and for severe covid-19 was 0.45 (0.13 to 1.55). The corresponding findings for household members of teachers were 0.91 (0.67 to 1.23) and 0.73 (0.37 to 1.44), and for patient facing healthcare workers were 2.08 (1.73 to 2.50) and 2.26 (1.43 to 3.59). Similar risks were seen for teachers in the second period, when schools reopened in summer 2021. These values were higher than those seen in spring/summer 2020, when schools were mostly closed. CONCLUSION: Compared with adults of working age who are otherwise similar, teachers and their household members were not found to be at increased risk of hospital admission with covid-19 and were found to be at lower risk of severe covid-19. These findings should reassure those who are engaged in face-to-face teaching.
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COVID-19/epidemiologia , Pessoal de Saúde/estatística & dados numéricos , Professores Escolares/estatística & dados numéricos , Adulto , Idoso , Estudos de Casos e Controles , Controle de Doenças Transmissíveis/métodos , Conjuntos de Dados como Assunto , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Medição de Risco , SARS-CoV-2 , Escócia/epidemiologia , Adulto JovemRESUMO
BACKGROUND: COVID-19 deaths are commoner among care-home residents, but the mortality burden has not been quantified. METHODS: Care-home residency was identified via a national primary care registration database linked to mortality data. Life expectancy was estimated using Makeham-Gompertz models to (i) describe yearly life expectancy from November 2015 to October 2020 (ii) compare life expectancy (during 2016-18) between care-home residents and the wider population and (iii) apply care-home life expectancy estimates to COVID-19 death counts to estimate years of life lost (YLL). RESULTS: Among care-home residents, life expectancy in 2015/16 to 2019/20 ranged from 2.7 to 2.3 years for women and 2.3 to 1.8 years for men. Age-sex-specific life expectancy in 2016-18 in care-home residents was lower than in the Scottish population (10 and 2.5 years in those aged 70 and 90, respectively). Applying care home-specific life expectancies to COVID-19 deaths yield mean YLLs for care-home residents of 2.6 and 2.2 for women and men, respectively. In total YLL care-home residents have lost 3,560 years in women and 2,046 years in men. Approximately half of deaths and a quarter of YLL attributed to COVID-19 were accounted for by the 5% of over-70s who were care-home residents. CONCLUSION: COVID-19 infection has led to the loss of substantial years of life in care-home residents aged 70 years and over in Scotland. Prioritising the 5% of older adults who are care-home residents for vaccination is justified not only in terms of total deaths, but also in terms of YLL.
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COVID-19 , Expectativa de Vida , Idoso , Causas de Morte , Feminino , Humanos , Masculino , Mortalidade , SARS-CoV-2 , Escócia/epidemiologiaRESUMO
OBJECTIVE: Children are relatively protected from COVID-19, due to a range of potential mechanisms. We investigated if contact with children also affords adults a degree of protection from COVID-19. DESIGN: Cohort study based on linked administrative data. SETTING: Scotland. STUDY POPULATION: All National Health Service Scotland healthcare workers and their household contacts as of March 2020. MAIN EXPOSURE: Number of young children (0-11 years) living in the participant's household. MAIN OUTCOMES: COVID-19 requiring hospitalisation, and any COVID-19 (any positive test for SARS-CoV-2) in adults aged ≥18 years between 1 March and 12 October 2020. RESULTS: 241 266, 41 198, 23 783 and 3850 adults shared a household with 0, 1, 2 and 3 or more young children, respectively. Over the study period, the risk of COVID-19 requiring hospitalisation was reduced progressively with increasing numbers of household children-fully adjusted HR (aHR) 0.93 per child (95% CI 0.79 to 1.10). The risk of any COVID-19 was similarly reduced, with the association being statistically significant (aHR per child 0.93; 95% CI 0.88 to 0.98). After schools reopened to all children in August 2020, no association was seen between exposure to young children and risk of any COVID-19 (aHR per child 1.03; 95% CI 0.92 to 1.14). CONCLUSION: Between March and October 2020, living with young children was associated with an attenuated risk of any COVID-19 and COVID-19 requiring hospitalisation among adults living in healthcare worker households. There was no evidence that living with young children increased adults' risk of COVID-19, including during the period after schools reopened.
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COVID-19/transmissão , Características da Família , Pessoal de Saúde , Adulto , COVID-19/diagnóstico , COVID-19/imunologia , Teste para COVID-19 , Criança , Pré-Escolar , Estudos de Coortes , Proteção Cruzada , Feminino , Hospitalização , Humanos , Lactente , Recém-Nascido , Masculino , Pandemias , Fatores de Risco , SARS-CoV-2 , Instituições Acadêmicas , Escócia/epidemiologiaRESUMO
OBJECTIVE: To assess the risk of hospital admission for coronavirus disease 2019 (covid-19) among patient facing and non-patient facing healthcare workers and their household members. DESIGN: Nationwide linkage cohort study. SETTING: Scotland, UK, 1 March to 6 June 2020. PARTICIPANTS: Healthcare workers aged 18-65 years, their households, and other members of the general population. MAIN OUTCOME MEASURE: Admission to hospital with covid-19. RESULTS: The cohort comprised 158 445 healthcare workers, most of them (90 733; 57.3%) being patient facing, and 229 905 household members. Of all hospital admissions for covid-19 in the working age population (18-65 year olds), 17.2% (360/2097) were in healthcare workers or their households. After adjustment for age, sex, ethnicity, socioeconomic deprivation, and comorbidity, the risk of admission due to covid-19 in non-patient facing healthcare workers and their households was similar to the risk in the general population (hazard ratio 0.81 (95% confidence interval 0.52 to 1.26) and 0.86 (0.49 to 1.51), respectively). In models adjusting for the same covariates, however, patient facing healthcare workers, compared with non-patient facing healthcare workers, were at higher risk (hazard ratio 3.30, 2.13 to 5.13), as were household members of patient facing healthcare workers (1.79, 1.10 to 2.91). After sub-division of patient facing healthcare workers into those who worked in "front door," intensive care, and non-intensive care aerosol generating settings and other, those in front door roles were at higher risk (hazard ratio 2.09, 1.49 to 2.94). For most patient facing healthcare workers and their households, the estimated absolute risk of hospital admission with covid-19 was less than 0.5%, but it was 1% and above in older men with comorbidity. CONCLUSIONS: Healthcare workers and their households contributed a sixth of covid-19 cases admitted to hospital. Although the absolute risk of admission was low overall, patient facing healthcare workers and their household members had threefold and twofold increased risks of admission with covid-19.
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Infecções por Coronavirus/epidemiologia , Família , Pessoal de Saúde/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Adolescente , Adulto , Idoso , Betacoronavirus , COVID-19 , Estudos de Coortes , Comorbidade , Feminino , Pessoal de Saúde/classificação , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Fatores de Risco , SARS-CoV-2 , Escócia/epidemiologia , Adulto JovemRESUMO
The threat posed by severe congenital abnormalities related to Zika virus (ZKV) infection during pregnancy has turned development of a ZKV vaccine into an emergency. Recent work suggests that the cytotoxic T lymphocyte (CTL) response to infection is an important defense mechanism in response to ZKV. Here, we develop the rationale and strategy for a new approach to developing cytotoxic T lymphocyte (CTL) vaccines for ZKV flavivirus infection. The proposed approach is based on recent studies using a protein structure computer model for HIV epitope selection designed to select epitopes for CTL attack optimized for viruses that exhibit antigenic drift. Because naturally processed and presented human ZKV T cell epitopes have not yet been described, we identified predicted class I peptide sequences on ZKV matching previously identified DNV (Dengue) class I epitopes and by using a Major Histocompatibility Complex (MHC) binding prediction tool. A subset of those met the criteria for optimal CD8+ attack based on physical chemistry parameters determined by analysis of the ZKV protein structure encoded in open source Protein Data File (PDB) format files. We also identified candidate ZKV epitopes predicted to bind promiscuously to multiple HLA class II molecules that could provide help to the CTL responses. This work suggests that a CTL vaccine for ZKV may be possible even if ZKV exhibits significant antigenic drift. We have previously described a microsphere-based CTL vaccine platform capable of eliciting an immune response for class I epitopes in mice and are currently working toward in vivo testing of class I and class II epitope delivery directed against ZKV epitopes using the same microsphere-based vaccine.
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Low B vitamin status is linked with human vascular disease. We employed a proteomic and biochemical approach to determine whether nutritional folate deficiency and/or hyperhomocysteinemia altered metabolic processes linked with atherosclerosis in ApoE null mice. Animals were fed either a control fat (C; 4 % w/w lard) or a high-fat [HF; 21 % w/w lard and cholesterol (0/15 % w/w)] diet with different B vitamin compositions for 16 weeks. Aorta tissue was prepared and global protein expression, B vitamin, homocysteine and lipoprotein status measured. Changes in the expression of aorta proteins were detected in response to multiple B vitamin deficiency combined with a high-fat diet (P < 0.05) and were strongly linked with lipoprotein concentrations measured directly in the aorta adventitia (P < 0.001). Pathway analysis revealed treatment effects in the aorta-related primarily to cytoskeletal organisation, smooth muscle cell adhesion and invasiveness (e.g., fibrinogen, moesin, transgelin, vimentin). Combined B vitamin deficiency induced striking quantitative changes in the expression of aorta proteins in atherosclerotic ApoE null mice. Deregulated expression of these proteins is associated with human atherosclerosis. Cellular pathways altered by B vitamin status included cytoskeletal organisation, cell differentiation and migration, oxidative stress and chronic inflammation. These findings provide new insight into the molecular mechanisms through which B vitamin deficiency may accelerate atherosclerosis.
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BACKGROUND: Ruminococcus flavefaciens is an important fibre-degrading bacterium found in the mammalian gut. Cellulolytic strains from the bovine rumen have been shown to produce complex cellulosome structures that are associated with the cell surface. R. flavefaciens 007 is a highly cellulolytic strain whose ability to degrade dewaxed cotton, but not Avicel cellulose, was lost following initial isolation in the variant 007S. The ability was recovered after serial subculture to give the cotton-degrading strain 007C. This has allowed us to investigate the factors required for degradation of this particularly recalcitrant form of cellulose. METHODOLOGY/PRINCIPAL FINDINGS: The major proteins associated with the bacterial cell surface and with the culture supernatant were analyzed for R. flavefaciens 007S and 007C grown with cellobiose, xylan or Avicel cellulose as energy sources. Identification of the proteins was enabled by a draft genome sequence obtained for 007C. Among supernatant proteins a cellulosomal GH48 hydrolase, a rubrerthyrin-like protein and a protein with type IV pili N-terminal domain were the most strongly up-regulated in 007C cultures grown on Avicel compared with cellobiose. Strain 007S also showed substrate-related changes, but supernatant expression of the Pil protein and rubrerythrin in particular were markedly lower in 007S than in 007C during growth on Avicel. CONCLUSIONS/SIGNIFICANCE: This study provides new information on the extracellular proteome of R. flavefaciens and its regulation in response to different growth substrates. Furthermore it suggests that the cotton cellulose non-degrading strain (007S) has altered regulation of multiple proteins that may be required for breakdown of cotton cellulose. One of these, the type IV pilus was previously shown to play a role in adhesion to cellulose in R. albus, and a related pilin protein was identified here for the first time as a major extracellular protein in R. flavefaciens.
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Proteínas de Bactérias/metabolismo , Celulossomas/metabolismo , Espaço Extracelular/metabolismo , Fímbrias Bacterianas/metabolismo , Regulação Bacteriana da Expressão Gênica , Proteoma/metabolismo , Ruminococcus/citologia , Ruminococcus/metabolismo , Proteínas de Bactérias/genética , Celulose/metabolismo , Fímbrias Bacterianas/genética , Hemeritrina/metabolismo , Família Multigênica , Proteoma/genética , Rubredoxinas/metabolismo , Ruminococcus/genética , Ruminococcus/crescimento & desenvolvimentoRESUMO
A methyl-deficient diet (MD) lacking folic acid and the associated methyl donors choline and methionine, fed to the laboratory rat during the periods of oocyte and embryo development, has been shown to programme glucose metabolism in the offspring. The hepatic proteome of the male offspring of female rats fed MD diets for 3 weeks prior to mating and for the first 5 days of gestation has been examined by 2-dimensional gel electrophoresis. Three groups of differentially abundant proteins associated with energy metabolism, amino acid metabolism and antioxidant defence were identified in the soluble proteins extracted from the liver from the MD offspring at both 6 and 12 months of age. Altered mitochondrial activity in other programming models leads to a similar pattern of differential protein abundance. Two of the differentially abundant proteins were identified as GAPDH and PGK-1 by mass spectrometry. Western blotting showed that there were multiple isoforms of both proteins with similar molecular weights but different isoelectric points. The differentially abundant spots reduced in the MD offspring corresponded to minor isoforms of GAPDH and PGK-1. The levels of PPAR-alpha, SREBP and glucocorticoid receptor mRNAs associated with other models of prenatal programming were unchanged in the MD offspring. The data suggest that a diet deficient in folic acid and associated methyl donors fed during the peri-conception and early preimplantation periods of mammalian development affects mitochondrial function in the offspring and that the posttranslational modification of proteins may be important.
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SCOPE: Olive products are rich in phenolic compounds, which are natural antioxidants in vitro. We tested the in vivo effects of alperujo, an olive production by-product, as well as hydroxytyrosol and 3,4-dihydroxyphenylglycol (DHPG) isolated from alperujo, on indices and pathways of oxidative and metabolic stress in a vitamin E-deficient rat model. METHODS AND RESULTS: Rats were fed a vitamin E-deficient diet for 10 weeks, followed by this diet supplemented with either 100 mg/kg diet dα-tocopherol, alperujo extract, hydroxytyrosol, or 10 mg/kg diet DHPG, for a further 2 weeks. We detected alperujo phenolics in tissues and blood, indicating they are bioavailable. Alperujo extract partially ameliorated elevated plasma levels of thiobarbituric acid reactive substances and also lowered plasma cholesterol levels, whereas hydroxytyrosol increased plasma triglyceride levels. Proteomics and subsequent network analysis revealed that hepatic mitochondrial aldehyde dehydrogenase (ALDH2), of which protein and activity levels were regulated by dα-tocopherol and olive phenolics, represents a novel central regulatory protein hub affected by the dietary interventions. CONCLUSION: The in vivo free radical scavenging properties of olive phenolics appear relatively modest in our model. But alternative mechanisms, including regulation of ALDH2, may represent relevant antioxidant mechanisms by which dietary olive phenolics could have beneficial impact on cardiovascular health.
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Antioxidantes/uso terapêutico , Fígado/metabolismo , Metoxi-Hidroxifenilglicol/análogos & derivados , Olea/química , Estresse Oxidativo , Álcool Feniletílico/análogos & derivados , Extratos Vegetais/uso terapêutico , Aldeído Desidrogenase/metabolismo , Aldeído-Desidrogenase Mitocondrial , Animais , Anticolesterolemiantes/economia , Anticolesterolemiantes/metabolismo , Anticolesterolemiantes/uso terapêutico , Antioxidantes/economia , Antioxidantes/metabolismo , Dieta/efeitos adversos , Suplementos Nutricionais/economia , Modelos Animais de Doenças , Indústria de Processamento de Alimentos/economia , Frutas/química , Hipolipemiantes/economia , Hipolipemiantes/metabolismo , Hipolipemiantes/uso terapêutico , Resíduos Industriais/análise , Resíduos Industriais/economia , Absorção Intestinal , Fígado/enzimologia , Masculino , Metoxi-Hidroxifenilglicol/metabolismo , Metoxi-Hidroxifenilglicol/uso terapêutico , Proteínas Mitocondriais/metabolismo , Álcool Feniletílico/metabolismo , Álcool Feniletílico/uso terapêutico , Extratos Vegetais/economia , Extratos Vegetais/metabolismo , Distribuição Aleatória , Ratos , Deficiência de Vitamina E/sangue , Deficiência de Vitamina E/etiologia , Deficiência de Vitamina E/metabolismo , Deficiência de Vitamina E/fisiopatologiaRESUMO
cis-9, trans-11-Conjugated linoleic acid (c9 t11 CLA) exerts anti-diabetic effects by improving systemic insulin sensitivity and inflammation. Levels of CLA in beef can be increased by feeding cattle on pasture. This study aimed to explore the efficacy of a CLA-rich diet (0.6% w/w c9 t11 CLA), presented as beef enriched with CLA or beef supplemented with synthetic CLA (c9 t11 CLA), for 28 days on molecular biomarkers of the metabolic syndrome, and adipose, hepatic, and skeletal muscle proteome in male ob/ob mice. Despite equal weight gain, CLA-fed mice had lower plasma glucose, insulin, non-esterified fatty acid, triacylglycerol and interleukin-6, and higher adiponectin concentrations than controls. c9 t11 CLA induced differential regulation of redox status across all tissues, and decreased hepatic and muscle endoplasmic reticulum stress. CLA also modulated mechanistic links between the actin cytoskeleton, insulin signalling, glucose transport and inflammation in the adipose tissue. In the liver and muscle, c9 t11 CLA improved metabolic flexibility through co-ordination between carbohydrate and energy metabolism. c9 t11 CLA may ameliorate systemic insulin sensitivity in obesity-induced diabetes by altering cellular stress and redox status, and modulating nutrient handling in key insulin-sensitive tissues through complex biochemical interplay among representative proteomic signatures.
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Expressão Gênica/efeitos dos fármacos , Hipoglicemiantes/administração & dosagem , Ácidos Linoleicos Conjugados/administração & dosagem , Obesidade/metabolismo , Adiponectina/sangue , Tecido Adiposo/metabolismo , Animais , Glicemia , Ácidos Graxos não Esterificados/sangue , Insulina/sangue , Resistência à Insulina , Interleucina-6/sangue , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Obesidade/complicações , Obesidade/genética , Triglicerídeos/sangueRESUMO
SCOPE: Natural dietary anti-obesogenic phytochemicals may help combat the rising global incidence of obesity. We aimed to identify key hepatic pathways targeted by anti-obsogenic ginger phytochemicals fed to mice. METHODS AND RESULTS: Weaning mice were fed a high-fat diet containing 6-gingerol (HFG), zerumbone (HFZ), a characterized rhizome extract of the ginger-related plant Alpinia officinarum Hance (high fat goryankang, HFGK) or no phytochemicals (high-fat control, HFC) for 6 wks and were compared with mice on a low-fat control diet (LFC). Increased adiposity in the HFC group, compared with the LFC group, was significantly (p<0.05) reduced in the HFG and HFGK groups without food intake being affected. Correlation network analysis, including a novel residuals analysis, was utilized to investigate relationships between liver proteomic data, lipid and cholesterol biomarkers and physiological indicators of adiposity. 6-Gingerol significantly increased plasma cholesterol but hepatic farnesyl diphosphate synthetase, which is involved in cholesterol biosynthesis was decreased, possibly by negative feedback. Acetyl-coenzyme A acyltransferase 1 and enoyl CoA hydratase, which participate in the ß-oxidation of fatty acids were significantly (p<0.05) increased by consumption of phytochemical-supplemented diets. CONCLUSION: Dietary ginger phytochemicals target cholesterol metabolism and fatty acid oxidation in mice, with anti-obesogenic but also hypercholesterolemic consequences.
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Fármacos Antiobesidade/farmacologia , Biomarcadores/análise , Dieta Hiperlipídica , Proteínas/metabolismo , Zingiber officinale/química , Acetil-CoA C-Aciltransferase/metabolismo , Adiposidade/efeitos dos fármacos , Alpinia/química , Animais , Peso Corporal/efeitos dos fármacos , Catecóis/farmacologia , Colesterol/sangue , Dieta com Restrição de Gorduras , Enoil-CoA Hidratase/metabolismo , Álcoois Graxos/farmacologia , Geraniltranstransferase/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/farmacologia , Análise de Componente Principal , Proteômica , Sesquiterpenos/farmacologiaRESUMO
Consumption of industrial trans fat raises the risk of cardiovascular disease, but it is unclear whether cis9,trans11-conjugated linoleic acid (CLA)--a trans fatty acid in dairy products--modulates disease development. We investigated the effects of complete diets providing 7% of energy as industrial trans fat or cis9, trans11 CLA, compared with oleic acid, on regulation of plasma proteins in 12 healthy men. Diets were provided for 3 wk each, in random order. Plasma was collected at the end of each 3 wk intervention period, depleted of its 12 most abundant proteins and analyzed by 2-DE. Principal component analysis of protein spot intensity values revealed that the nature of the dietary intervention did not significantly affect the plasma proteome. The intervention provided in the 1st period produced a significant treatment effect compared with the interventions provided in the other two periods, and there was a significant subject effect. In conclusion, the nature of an extreme dietary intervention, i.e. 7% of energy provided by industrial trans fat or cis9,trans11 CLA, did not markedly affect the plasma proteome. Thus plasma proteomics using 2-DE appears, by and large, an unsuitable approach to detect regulation of plasma proteins due to changes in the diet.
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Proteínas Sanguíneas/metabolismo , Dieta , Ácidos Oleicos/metabolismo , Proteoma/metabolismo , Ácidos Graxos trans/metabolismo , Adulto , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/urina , Laticínios , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
PURPOSE: Platelets play a key role in haemostasis and wound healing, contributing to formation of vascular plugs. They are also involved in formation of atherosclerosic plaques. Some traditional diets, like the Mediterranean diet, are associated with a lower risk of cardiovascular disease. Components in these diets may have anti-platelet functions contributing to their health benefits. METHODS: We studied the effects of alperujo extract, an olive oil production waste product containing the majority of polyphenols found in olive fruits, through measurement of effects on platelet aggregation and activation in isolated human platelets, and through identification of changes in the platelet proteome. RESULTS: Alperujo extract (40 mg/L) significantly decreased in vitro ADP- (p = 0.002) and TRAP- (p = 0.02) induced platelet activation as measured by the flow cytometry using the antibody for p-selectin (CD62p), but it did not affect the conformation of the fibrinogen receptor as measured by flow cytometry using the antibodies for anti-fibrinogen, CD42a and CD42b. Alperujo extract (100 mg/L) inhibited both collagen- and TRAP-induced platelet aggregation by 5% (p < 0.05), and a combination of hydroxytyrosol and 3,4-dihydroxyphenylglycol were, at least partly, responsible for this effect. Proteomic analysis identified nine proteins that were differentially regulated by the alperujo extract upon ADP-induced platelet aggregation. These proteins represent important mechanisms that may underlie the anti-platelet effects of this extract: regulation of platelet structure and aggregation, coagulation and apoptosis, and signalling by integrin αIIb/ß3. CONCLUSIONS: Alperujo extract may protect against platelet activation, platelet adhesion and possibly have anti-inflammatory properties.
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Plaquetas/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/farmacologia , Óleos de Plantas/farmacologia , Polifenóis/farmacologia , Proteômica/métodos , Anticorpos , Coagulação Sanguínea/efeitos dos fármacos , Colágeno/metabolismo , Feminino , Fibrinogênio/efeitos dos fármacos , Humanos , Masculino , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/metabolismo , Azeite de Oliva , Selectina-P/efeitos dos fármacos , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/metabolismo , Adesividade Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismoRESUMO
BACKGROUND: Elevated leptin levels in obesity are associated with increased risk of colon pathology, implicating leptin signaling in colon disease. However, leptin-regulated processes in the colon are currently uncharacterized. Previously, we demonstrated that leptin receptors are expressed on colon epithelium and that increased adiposity and elevated plasma leptin in rats are associated with perturbed metabolism in colon tissue. Thus, we hypothesize that obesity disrupts expression of proteins regulated by leptin in the colon. METHODS: A proteomic analysis was conducted to investigate firstly, differences in the colon of mice lacking leptin and leptin signaling (ob/ob and db/db, respectively) by comparing protein expression profiles with wild-type mice. Secondly, responses to leptin challenge in wild-type mice and ob/ob mice were compared to identify leptin-regulated proteins and associated cellular processes. RESULTS: Forty proteins were identified with significantly altered expression patterns associated with differences in leptin status in comparisons between all groups of mice. These proteins are associated with calcium binding, cell cycle, cell proliferation, electron transport chain, energy metabolism, protein folding and transport, redox regulation, structural proteins, and proteins involved in transport and regulation of mucus production. CONCLUSIONS: This study provides evidence that obesity and leptin significantly alter protein profiles of a number of proteins linked to cellular processes in colon tissues that may be linked to the increased risk of colon pathology associated with obesity.
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Colo/metabolismo , Leptina/metabolismo , Obesidade/metabolismo , Animais , Colo/efeitos dos fármacos , Perfilação da Expressão Gênica , Leptina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteômica , Receptores para Leptina/metabolismoRESUMO
Clear cell renal cell carcinoma (ccRCC), a tubular epithelial cell (TEC) malignancy, frequently secretes tumor necrosis factor (TNF). TNF signals via two distinct receptors (TNFRs). TNFR1, expressed in normal kidney primarily on endothelial cells, activates apoptotic signaling kinase 1 and nuclear factor-kappaB (NF-kappaB) and induces cell death, whereas TNFR2, inducibly expressed on endothelial cells and on TECs by injury, activates endothelial/epithelial tyrosine kinase (Etk), which trans-activates vascular endothelial growth factor receptor 2 (VEGFR2) to promote cell proliferation. We investigated TNFR expression in clinical samples and function in short-term organ cultures of ccRCC tissue treated with wild-type TNF or specific muteins selective for TNFR1 (R1-TNF) or TNFR2 (R2-TNF). There is a significant increase in TNFR2 but not TNFR1 expression on malignant TECs that correlates with increasing malignant grade. In ccRCC organ cultures, R1-TNF increases TNFR1, activates apoptotic signaling kinase and NF-kappaB, and promotes apoptosis in malignant TECs. R2-TNF increases TNFR2, activates NF-kappaB, Etk, and VEGFR2 and increases entry into the cell cycle. Wild-type TNF induces both sets of responses. R2-TNF actions are blocked by pretreatment with a VEGFR2 kinase inhibitor. We conclude that TNF, acting through TNFR2, is an autocrine growth factor for ccRCC acting via Etk-VEGFR2 cross-talk, insights that may provide a more effective therapeutic approach to this disease.
Assuntos
Carcinoma de Células Renais/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais/fisiologia , Idoso , Animais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Ciclo Celular/fisiologia , Ativação Enzimática , Feminino , Humanos , MAP Quinase Quinase Quinase 5/genética , MAP Quinase Quinase Quinase 5/metabolismo , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo II do Fator de Necrose Tumoral/genética , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
We used plasma proteomics to identify human proteins responsive to folate status. Plasma was collected from subjects treated with placebo or 1.2 mg of folic acid daily for 12 weeks in a randomized controlled trial. Homocysteine and folate were measured by immunoassay and uracil misincorporation by electrophoresis. The plasma proteome was assessed by 2-D gel electrophoresis, and proteins were identified by LC MS/MS. 5-methylTHF increased 5-fold (P = 0.000003) in response to intervention. Red cell folate doubled (P = 0.013), and lymphocyte folate increased 44% (P = 0.0001). Hcy and uracil dropped 22% (P = 0.0005) and 25% (P = 0.05), respectively. ApoE A-1, alpha-1-antichymotrypsin, antithrombin, and serum amyloid P were downregulated, while albumin, IgM C, and complement C3 were upregulated (P < 0.05). More than 60 proteins were significantly associated with folate pre- and postintervention (P < 0.01). These were categorized into metabolic pathways related to complement fixation (e.g., C1, C3, C4, Factor H, Factor 1, Factor B, clusterin), coagulation (e.g., antithrombin, alpha-1-antitrypsin, kininogen) and mineral transport (e.g., transthyretin, haptoglobin, ceruloplasmin). Low folate status pre- and post-treatment were associated with lower levels of proteins involved in activation and regulation of immune function and coagulation. Supplementation with synthetic folic acid increased expression of these proteins but did not substantially disrupt the balance of these pathways.
Assuntos
Proteínas Sanguíneas/metabolismo , Ácido Fólico/administração & dosagem , Ácido Fólico/sangue , Proteoma/metabolismo , Proteômica/métodos , Adulto , Coagulação Sanguínea , Proteínas Sanguíneas/química , Suplementos Nutricionais , Esquema de Medicação , Feminino , Homocisteína/sangue , Homocisteína/metabolismo , Humanos , Imunidade/imunologia , Inflamação/sangue , Inflamação/imunologia , Masculino , Proteoma/efeitos dos fármacos , S-Adenosilmetionina/sangue , S-Adenosilmetionina/metabolismo , Tetra-Hidrofolatos/sangue , Tetra-Hidrofolatos/metabolismoRESUMO
Long-chain n-3 PUFA from fish oil protect against death from CHD but mechanisms are not well understood. Preliminary results indicate that fish oil may affect the enzyme soluble epoxide hydrolase (sEH) and influence inflammatory pathways in a time-dependent manner. In the present study male apoE knockout (Apoe-/-) mice were randomised to three dietary groups receiving a high-fat high-cholesterol diet supplemented with 2 % (w/w) high-oleic acid sunflower-seed (HOSF) oil, DHA oil or fish oil. Livers and proximal aortas were collected on day 2 and on weeks 1, 2, 4 and 10 to determine hepatic sEH levels, hepatic fatty acid composition, hepatic proteome and atherosclerotic plaque size in the aortic root. Intervention with fish oil, but not with DHA, resulted in significantly lower levels of hepatic sEH levels with time compared with HOSF oil. DHA and fish oil caused differential regulation of thirty-five hepatic proteins which were mainly involved in lipoprotein metabolism and oxidative stress. All mice developed atherosclerosis without differences in plaque size between the three groups. Thus EPA may be responsible for lowering levels of hepatic sEH and both fish oil and DHA could beneficially affect lipoprotein metabolism and oxidative stress.
Assuntos
Apolipoproteínas E/deficiência , Aterosclerose/patologia , Colesterol na Dieta/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Epóxido Hidrolases/metabolismo , Óleos de Peixe/farmacologia , Fígado/enzimologia , Ácido Oleico/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/enzimologia , Aterosclerose/prevenção & controle , Primers do DNA , Gorduras na Dieta , Ácidos Docosa-Hexaenoicos/administração & dosagem , Epóxido Hidrolases/genética , Óleos de Peixe/administração & dosagem , Proteína Forkhead Box O3 , Fatores de Transcrição Forkhead/genética , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteômica , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sementes , Especificidade da EspécieRESUMO
Protein-bound pyrroles are a sign of oxidative damage. Here we report a specific method for detecting pyrrole-containing proteins using biotin-labeled Ehrlich's reagent (ER-B). After treatment of either human serum or isolated human serum proteins with various oxidizing agents, damaged, biotin-labeled components could be detected by blotting. Combining the use of ER-B with proteomic techniques allowed human serum proteins susceptible to oxidative damage to be detected and then identified by LC/MS/MS. Identification of such proteins in different human conditions such as obesity, diabetes, and cardiovascular disease should lead to the discovery of new biomarkers and the development of specific assays to monitor health status.
Assuntos
Benzaldeídos/química , Biotina/análogos & derivados , Proteínas Sanguíneas/química , Proteômica/métodos , Pirróis/química , Biotina/química , Proteínas Sanguíneas/isolamento & purificação , Proteínas Sanguíneas/metabolismo , Western Blotting , Cromatografia Líquida de Alta Pressão , Eletroforese em Gel Bidimensional , Humanos , Indicadores e Reagentes/química , Estresse Oxidativo , Pirróis/análise , Espectrometria de Massas em TandemRESUMO
Previously we have examined the effects of diets deficient in folic acid ( - F) or folate deficient with low methionine and choline ( - F LM LC) on the relative abundance of soluble proteins in the liver of the pregnant rat. In the present study we report the corresponding changes in the fetal liver at day 21 of gestation. The abundance of eighteen proteins increased when dams were fed the - F diet. When dams were fed the - F LM LC diet, thirty-three proteins increased and eight decreased. Many of the differentially abundant proteins in the fetal liver could be classified into the same functional groups as those previously identified in the maternal liver, namely protein synthesis, metabolism, lipid metabolism and proteins associated with the cytoskeleton and endoplasmic reticulum. The pattern was consistent with reduced cell proliferation in the - F LM LC group but not in the - F group. Metabolic enzymes associated with lipid metabolism changed in both the - F and - F LM LC groups. The mRNA for carnitine palmitoyl transferase were up-regulated and CD36 (fatty acid translocase) down-regulated in the - F group, suggesting increased mitochondrial oxidation of fatty acids as an indirect response to altered maternal lipid metabolism. In the - F LM LC group the mRNA for acetyl CoA carboxylase was down-regulated, suggesting reduced fatty acid synthesis. The mRNA for transcriptional regulators including PPARalpha and sterol response element-binding protein-1c were unchanged. These results suggest that an adequate supply of folic acid and the related methyl donors may benefit fetal development directly by improving lipid metabolism in fetal as well as maternal tissues.