RESUMO
BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) demonstrate nutritional selenium deficiencies and are at greater risk of developing colon cancer. Previously, we determined that global reduction of the secreted antioxidant selenium-containing protein, selenoprotein P (SELENOP), substantially increased tumor development in an experimental colitis-associated cancer (CAC) model. We next sought to delineate tissue-specific contributions of SELENOP to intestinal inflammatory carcinogenesis and define clinical context. METHODS: Selenop floxed mice crossed with Cre driver lines to delete Selenop from the liver, myeloid lineages, or intestinal epithelium were placed on an azoxymethane/dextran sodium sulfate experimental CAC protocol. SELENOP loss was assessed in human ulcerative colitis (UC) organoids, and expression was queried in human and adult UC samples. RESULTS: Although large sources of SELENOP, both liver- and myeloid-specific Selenop deletion failed to modify azoxymethane/dextran sodium sulfate-mediated tumorigenesis. Instead, epithelial-specific deletion increased CAC tumorigenesis, likely due to elevated oxidative stress with a resulting increase in genomic instability and augmented tumor initiation. SELENOP was down-regulated in UC colon biopsies and levels were inversely correlated with endoscopic disease severity and tissue S100A8 (calprotectin) gene expression. CONCLUSIONS: Although global selenium status is typically assessed by measuring liver-derived plasma SELENOP levels, our results indicate that the peripheral SELENOP pool is dispensable for CAC. Colonic epithelial SELENOP is the main contributor to local antioxidant capabilities. Thus, colonic SELENOP is the most informative means to assess selenium levels and activity in IBD patients and may serve as a novel biomarker for UC disease severity and identify patients most predisposed to CAC development.
Assuntos
Colite Ulcerativa/metabolismo , Neoplasias Associadas a Colite/prevenção & controle , Colite/metabolismo , Colo/metabolismo , Mucosa Intestinal/metabolismo , Estresse Oxidativo , Selenoproteína P/metabolismo , Adolescente , Animais , Azoximetano , Estudos de Casos e Controles , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Criança , Pré-Escolar , Colite/induzido quimicamente , Colite/genética , Colite Ulcerativa/genética , Neoplasias Associadas a Colite/induzido quimicamente , Neoplasias Associadas a Colite/genética , Neoplasias Associadas a Colite/metabolismo , Colo/patologia , Dano ao DNA , Sulfato de Dextrana , Modelos Animais de Doenças , Feminino , Instabilidade Genômica , Humanos , Mucosa Intestinal/patologia , Fígado/metabolismo , Masculino , Camundongos Knockout , Células Mieloides/metabolismo , Selenoproteína P/genéticaRESUMO
Selenoprotein P (SELENOP) is a major selenoenzyme in plasma and linked to antioxidant properties and possibly to lung cancer; however, supporting evidence is limited. We investigated the association between pre-diagnostic plasma SELENOP concentration and lung cancer risk in a case-control study of 403 cases and 403 individually matched controls nested within the Shanghai Men's Health Study. SELENOP concentration in pre-diagnostic plasma samples was measured by a sandwich enzyme-linked immunosorbent assay. Cases were diagnosed with lung cancer between 2003 and 2010. Multivariate conditional logistic regression was used to estimate odds ratios (OR) and the corresponding 95% confidence intervals (CI) for studying the association between plasma SELENOP concentration and lung cancer risk. Cases had slightly lower plasma SELENOP concentration than controls (4.3 ± 1.2 versus 4.4 ± 1.1 mg/l, P difference = 0.09). However, the multivariate analysis showed no association between plasma SELENOP concentration and lung cancer risk among all participants (OR = 1.08, 95% CI = 0.54-2.14 for quartile 4 versus quartile 1), or by smoking status or tumor aggressiveness. In contrast, although the number of cases was limited, plasma SELENOP concentration was positively associated with lung adenocarcinoma risk (OR = 5.38, 95% CI = 1.89-15.35 for tertile 3 versus tertile 1), but not with squamous cell lung carcinoma (OR = 1.69, 95% CI = 0.43-6.70). Our study of adult men living in selenium non-deficient areas in China provides little support for the inverse association between pre-diagnostic plasma SELENOP concentration and lung cancer risk. Our finding of a positive association with risk of lung adenocarcinoma needs to be interpreted with caution.
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Adenocarcinoma de Pulmão/sangue , Neoplasias Pulmonares/sangue , Saúde do Homem/estatística & dados numéricos , Neoplasias de Células Escamosas/sangue , Selênio/sangue , Selenoproteína P/sangue , Adenocarcinoma de Pulmão/epidemiologia , Adulto , Idoso , Estudos de Casos e Controles , China/epidemiologia , Ensaio de Imunoadsorção Enzimática , Humanos , Modelos Logísticos , Neoplasias Pulmonares/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias de Células Escamosas/epidemiologia , Estudos Prospectivos , Risco , Fumar/efeitos adversosRESUMO
Selenium is regulated in the body to maintain vital selenoproteins and to avoid toxicity. When selenium is limiting, cells utilize it to synthesize the selenoproteins most important to them, creating a selenoprotein hierarchy in the cell. The liver is the central organ for selenium regulation and produces excretory selenium forms to regulate whole-body selenium. It responds to selenium deficiency by curtailing excretion and secreting selenoprotein P (Sepp1) into the plasma at the expense of its intracellular selenoproteins. Plasma Sepp1 is distributed to tissues in relation to their expression of the Sepp1 receptor apolipoprotein E receptor-2, creating a tissue selenium hierarchy. N-terminal Sepp1 forms are taken up in the renal proximal tubule by another receptor, megalin. Thus, the regulated whole-body pool of selenium is shifted to needy cells and then to vital selenoproteins in them to supply selenium where it is needed, creating a whole-body selenoprotein hierarchy.
Assuntos
Homeostase/fisiologia , Selênio/metabolismo , Animais , Disponibilidade Biológica , Transporte Biológico , Biomarcadores , Dieta , Suplementos Nutricionais , Nível de Saúde , Humanos , Túbulos Renais Proximais/metabolismo , Proteínas Relacionadas a Receptor de LDL/fisiologia , Fígado/fisiologia , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/fisiologia , Necessidades Nutricionais , Especificidade de Órgãos , Selênio/deficiência , Selênio/farmacocinética , Selenocisteína/metabolismo , Selenometionina/metabolismo , Selenoproteína P/análise , Selenoproteína P/sangue , Selenoproteínas/biossíntese , Selenoproteínas/metabolismoRESUMO
Sepp1 supplies selenium to tissues via receptor-mediated endocytosis. Mice, rats, and humans have 10 selenocysteines in Sepp1, which are incorporated via recoding of the stop codon, UGA. Four isoforms of rat Sepp1 have been identified, including full-length Sepp1 and three others, which terminate at the second, third, and seventh UGA codons. Previous studies have shown that the longer Sepp1 isoforms bind to the low density lipoprotein receptor apoER2, but the mechanism remains unclear. To identify the essential residues for apoER2 binding, an in vitro Sepp1 binding assay was developed using different Sec to Cys substituted variants of Sepp1 produced in HEK293T cells. ApoER2 was found to bind the two longest isoforms. These results suggest that Sepp1 isoforms with six or more selenocysteines are taken up by apoER2. Furthermore, the C-terminal domain of Sepp1 alone can bind to apoER2. These results indicate that apoER2 binds to the Sepp1 C-terminal domain and does not require the heparin-binding site, which is located in the N-terminal domain. Site-directed mutagenesis identified three residues of Sepp1 that are necessary for apoER2 binding. Sequential deletion of extracellular domains of apoER2 surprisingly identified the YWTD ß-propeller domain as the Sepp1 binding site. Finally, we show that apoER2 missing the ligand-binding repeat region, which can result from cleavage at a furin cleavage site present in some apoER2 isoforms, can act as a receptor for Sepp1. Thus, longer isoforms of Sepp1 with high selenium content interact with a binding site distinct from the ligand-binding domain of apoER2 for selenium delivery.
Assuntos
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/química , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Selênio/metabolismo , Selenoproteína P/metabolismo , Sequência de Aminoácidos , Animais , Endocitose , Feminino , Células HEK293 , Humanos , Ligantes , Masculino , Camundongos , Dados de Sequência Molecular , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Selenocisteína/metabolismo , Selenoproteína P/química , Alinhamento de Sequência , Especificidade por SubstratoRESUMO
Selenoprotein P (Sepp1) and its receptor, apolipoprotein E receptor 2 (apoER2), account for brain retaining selenium better than other tissues. The primary sources of Sepp1 in plasma and brain are hepatocytes and astrocytes, respectively. ApoER2 is expressed in varying amounts by tissues; within the brain it is expressed primarily by neurons. Knockout of Sepp1 or apoER2 lowers brain selenium from â¼120 to â¼50 ng/g and leads to severe neurodegeneration and death in mild selenium deficiency. Interactions of Sepp1 and apoER2 that protect against this injury have not been characterized. We studied Sepp1, apoER2, and brain selenium in knockout mice. Immunocytochemistry showed that apoER2 mediates Sepp1 uptake at the blood-brain barrier. When Sepp1(-/-) or apoER2(-/-) mice developed severe neurodegeneration caused by mild selenium deficiency, brain selenium was â¼35 ng/g. In extreme selenium deficiency, however, brain selenium of â¼12 ng/g was tolerated when both Sepp1 and apoER2 were intact in the brain. These findings indicate that tandem Sepp1-apoER2 interactions supply selenium for maintenance of brain neurons. One interaction is at the blood-brain barrier, and the other is within the brain. We postulate that Sepp1 inside the blood-brain barrier is taken up by neurons via apoER2, concentrating brain selenium in them.
Assuntos
Barreira Hematoencefálica/fisiologia , Encéfalo/metabolismo , Proteínas Relacionadas a Receptor de LDL/fisiologia , Degeneração Neural/prevenção & controle , Selênio/metabolismo , Selenoproteína P/fisiologia , Animais , Animais Congênicos , Transporte Biológico , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Capilares/metabolismo , Plexo Corióideo/embriologia , Plexo Corióideo/crescimento & desenvolvimento , Plexo Corióideo/metabolismo , Endocitose , Células Endoteliais/metabolismo , Feminino , Proteínas Relacionadas a Receptor de LDL/deficiência , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Degeneração Neural/etiologia , Degeneração Neural/metabolismo , Neurônios/metabolismo , Gravidez , Selênio/administração & dosagem , Selênio/deficiência , Selênio/farmacocinética , Selenoproteína P/deficiênciaRESUMO
Selenoprotein P (Sepp1) is taken up by receptor-mediated endocytosis for its selenium. The other extracellular selenoprotein, glutathione peroxidase-3 (Gpx3), has not been shown to transport selenium. Mice with genetic alterations of Sepp1, the Sepp1 receptors apolipoprotein E receptor-2 (apoER2) and megalin, and Gpx3 were used to investigate maternal-fetal selenium transfer. Immunocytochemistry (ICC) showed receptor-independent uptake of Sepp1 and Gpx3 in the same vesicles of d-13 visceral yolk sac cells, suggesting uptake by pinocytosis. ICC also showed apoER2-mediated uptake of maternal Sepp1 in the d-18 placenta. Thus, two selenoprotein-dependent maternal-fetal selenium transfer mechanisms were identified. Selenium was quantified in d-18 fetuses with the mechanisms disrupted. Maternal Sepp1 deletion, which lowers maternal whole-body selenium, decreased fetal selenium under selenium-adequate conditions but deletion of fetal apoER2 did not. Fetal apoER2 deletion did decrease fetal selenium, by 51%, under selenium-deficient conditions, verifying function of the placental Sepp1-apoER2 mechanism. Maternal Gpx3 deletion decreased fetal selenium, by 13%, but only under selenium-deficient conditions. These findings indicate that the selenoprotein uptake mechanisms ensure selenium transfer to the fetus under selenium-deficient conditions. The failure of their disruptions (apoER2 deletion, Gpx3 deletion) to affect fetal selenium under selenium-adequate conditions indicates the existence of an additional maternal-fetal selenium transfer mechanism.
Assuntos
Glutationa Peroxidase/metabolismo , Proteínas Relacionadas a Receptor de LDL/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Troca Materno-Fetal/fisiologia , Selênio/metabolismo , Selenoproteína P/metabolismo , Animais , Transporte Biológico , Feminino , Glutationa Peroxidase/genética , Imuno-Histoquímica , Proteínas Relacionadas a Receptor de LDL/genética , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Masculino , Troca Materno-Fetal/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia de Fluorescência , Placenta/embriologia , Placenta/metabolismo , Gravidez , Selenoproteína P/genética , Fatores de Tempo , Saco Vitelino/embriologia , Saco Vitelino/metabolismoRESUMO
Protistan oyster parasites in the genus Bonamia have been observed in recent years infecting new hosts on five continents, with most of these parasites genetically similar to austral species Bonamia exitiosa and Bonamia roughleyi. Identification of the newly observed parasites as one or another of these described species has been complicated by the fact that B. exitiosa and B. roughleyi are phylogenetically indistinguishable at the small-subunit ribosomal DNA (SSU rDNA) level, with samples of B. roughleyi type material no longer available for genetic re-analyses using more informative internal transcribed spacer (ITS) region DNA sequences. To resolve this issue, we evaluated B. roughleyi in field collections of hosts Saccostrea glomerata and Ostrea angasi (as well as Crassostrea gigas) in New South Wales, Australia in 2006 and 2007, and re-analyzed histological samples from the original description of this parasite species using in situ hybridization. Despite (1) reports of the oyster disease putatively caused by B. roughleyi during the time of collections, (2) the observation of gross lesions characteristic of the disease, and (3) the observation of B. roughleyi cells in association with the lesions, we detected a Bonamia sp. by PCR in just 1/42 O. angasi (2.4%), and 1/608 S. glomerata (0.2%), the latter oyster of which is the type host. SSU rDNA sequences of the amplicons were nearly identical to those of B. exitiosa and B. roughleyi, and phylogenetic analysis of ITS region sequences placed them on a B. exitiosa clade. A Haplosporidium sp. sequence similar to that of H. costale was PCR-amplified from nearly half the S. glomerata and O. angasi, but no Haplosporidium sp. was observed histologically. Our inability to identify a Bonamia sp. sequence in association with the B. roughleyi observed histologically suggests that this parasite is not a Bonamia sp. at all, and should be regarded as B. roughleyi nomen dubium. We conclude that the Bonamia sp. that we and other investigators detected in southeastern Australian S. glomerata and O. angasi was B. exitiosa.
Assuntos
Haplosporídios/genética , Ostreidae/parasitologia , Animais , Austrália , DNA de Protozoário/análise , DNA de Protozoário/genética , DNA Ribossômico/análise , DNA Ribossômico/genética , Hibridização In Situ , Filogenia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The genus Bonamia (Haplosporidia) includes economically significant oyster parasites. Described species were thought to have fairly circumscribed host and geographic ranges: B. ostreae infecting Ostrea edulis in Europe and North America, B. exitiosa infecting O. chilensis in New Zealand, and B. roughleyi infecting Saccostrea glomerata in Australia. The discovery of B. exitiosa-like parasites in new locations and the observation of a novel species, B. perspora, in non-commercial O. stentina altered this perception and prompted our wider evaluation of the global diversity of Bonamia parasites. Samples of 13 oyster species from 21 locations were screened for Bonamia spp. by PCR, and small subunit and internal transcribed spacer regions of Bonamia sp. ribosomal DNA were sequenced from PCR-positive individuals. Infections were confirmed histologically. Phylogenetic analyses using parsimony and Bayesian methods revealed one species, B. exitiosa, to be widely distributed, infecting 7 oyster species from Australia, New Zealand, Argentina, eastern and western USA, and Tunisia. More limited host and geographic distributions of B. ostreae and B. perspora were confirmed, but nothing genetically identifiable as B. roughleyi was found in Australia or elsewhere. Newly discovered diversity included a Bonamia sp. in Dendostrea sandvicensis from Hawaii, USA, that is basal to the other Bonamia species and a Bonamia sp. in O. edulis from Tomales Bay, California, USA, that is closely related to both B. exitiosa and the previously observed Bonamia sp. from O. chilensis in Chile.
Assuntos
DNA Espaçador Ribossômico/genética , Haplosporídios/genética , Haplosporídios/fisiologia , Ostreidae/parasitologia , Filogenia , Animais , Variação Genética , Interações Hospedeiro-Parasita , Ostreidae/genética , Especificidade da EspécieRESUMO
Multiple sclerosis (MS) is a chronic central nervous system (CNS) neurodegenerative and neuroinflammatory disease marked by a host immune reaction that targets and destroys the neuronal myelin sheath. MS and correlating animal disease models show comorbidities, including intestinal barrier disruption and alterations of the commensal microbiome. It is accepted that diet plays a crucial role in shaping the microbiota composition and overall gastrointestinal (GI) tract health, suggesting an interplay between nutrition and neuroinflammation via the gut-brain axis. Unfortunately, poor host health and diet lead to microbiota modifications that could lead to significant responses in the host, including inflammation and neurobehavioral changes. Beneficial microbial metabolites are essential for host homeostasis and inflammation control. This review will highlight the importance of the gut microbiota in the context of host inflammatory responses in MS and MS animal models. Additionally, microbial community restoration and how it affects MS and GI barrier integrity will be discussed.
RESUMO
INTRODUCTION: This analysis sought to identify disparities in social determinants of health (SDOH) outcomes at a Texas pediatric hospital. METHODS: This retrospective study used electronic health records of pediatric patients families surveyed August -December 2022. Outcomes for health literacy, social support, food, transportation, energy, digital, and housing insecurity, and tobacco exposure were analyzed across demographic categories. RESULTS: Among 15,294 respondents to the survey (mean child age, 8.73 years; 43.68% Hispanic, 29.73% non-Hispanic White, 18.27% non-Hispanic Black, 6.79% other race/ethnicity; 53.95% male), 50.25% of respondents reported at least one SDOH, whereas 23.39% reported two or more SDOH. The most prevalent SDOH was lack of social support (3,456, 23.91%). Hispanic, non-Hispanic Black, and other race/ethnicity respondents, non-English speakers, and public insurance users had higher odds of reporting almost all SDOH in logistic regression models adjusted for age, race/ethnicity, language, gender, and insurance type. DISCUSSION: Race/ethnicity, language, and insurance type disparities were identified for all SDOH.
Assuntos
Pediatria , Determinantes Sociais da Saúde , Disparidades Socioeconômicas em Saúde , Criança , Feminino , Humanos , Masculino , Registros Eletrônicos de Saúde , Etnicidade , Estudos Retrospectivos , Grupos RaciaisRESUMO
BACKGROUND: Household food insecurity (FI) is a modifiable social determinant of health linked to chronic health outcomes. Little is known, however, about the prevalence of metabolic syndrome (MetS) in pediatric population-based studies by household FI status. OBJECTIVES: The objective of the study was to estimate the prevalence of the MetS by household FI status over the past 2 decades. METHODS: This cross-sectional study used data from the 2001-2020 National Health and Nutrition Examination Survey (NHANES). Participants were nonpregnant adolescents ages 12- 18 y in United States. The prevalence of MetS [elevated waist circumference and >2 of the following risk factors: elevated blood pressure, and fasting glucose, triglyceride, and/or low high-density lipoprotein (HDL) cholesterol concentrations] by FI status was evaluated using chi-square and logistic regression analyses. RESULTS: The estimated prevalence of MetS was 2.66% [95% confidence interval (CI): 2.28%, 3.09%] in the final analytical sample (unweighted N = 12,932). A total of 3.39% (95% CI: 2.53%, 4.53%) of adolescents from FI households had MetS compared to 2.48% (95% CI: 2.11%, 2.9%) among adolescents with no household FI. Hispanic adolescents had the highest prevalence of MetS (3.73%, 95% CI: 3.05, 4.56) compared with adolescents who identified as non-Hispanic White (2.78%, 95% CI: 2.25, 3.43), non-Hispanic Black (1.58%, 95% CI: 1.19, 2.10). Adolescents with household FI (23.20%) were more likely to have MetS [odds ratio (OR): 1.38; 95% CI: 1.02, 1.88; I=0.039) compared with adolescents with no household FI, but in fully adjusted models this was not significant (OR: 1.13; 95% CI: 0.75, 1.72). CONCLUSIONS: Using the most current NHANES data, the estimated prevalence of MetS in adolescents in United States was slightly higher among those from FI households. However, after adjusting for potential confounders, the relationship between household FI and MetS was nonsignificant, highlighting the complexity of factors contributing to MetS in this population. Hispanic adolescents share a disproportionate burden of MetS compared with their non-Hispanic counterparts.
Assuntos
Síndrome Metabólica , Humanos , Criança , Adolescente , Estados Unidos/epidemiologia , Síndrome Metabólica/epidemiologia , Inquéritos Nutricionais , Estudos Transversais , Fatores de Risco , Prevalência , Insegurança AlimentarRESUMO
Obesity is a pandemic that disproportionately affects children from vulnerable populations in the USA. Current treatment approaches in primary care settings in the USA have been reported to be insufficient at managing pediatric obesity, primarily due to implementation challenges for healthcare systems and barriers for families. While the literature has examined the efficacy of pediatric obesity interventions focused on internal validity, it lacks sufficient reporting and analysis of external validity necessary for successful translation to primary care settings. We conducted a systematic review of the primary-care-setting literature from January 2007 to March 2020 on family-based pediatric weight management interventions in both English and/or Spanish for children ages 6-12 years in the USA using the Reach, Efficacy/Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework. A literature search, using PRISMA guidelines, was conducted in January 2022 using the following electronic databases: Medline Ovid, Embase, and Cochrane Library. 22 270 records were screened, and 376 articles were reviewed in full. 184 studies were included. The most commonly reported dimensions of the RE-AIM framework were Reach (65%), Efficacy/Effectiveness (64%), and Adoption (64%), while Implementation (47%) and Maintenance (42%) were less often reported. The prevalence of reporting RE-AIM construct indicators ranged greatly, from 1% to 100%. This systematic review underscores the need for more focus on external validity to guide the development, implementation, and dissemination of future pediatric obesity interventions based in primary care settings. It also suggests conducting additional research on sustainable financing for pediatric obesity interventions.
Pediatric weight management research focused on primary care centers for children ages 612 in the USA has typically focused on assessing the effectiveness of the intervention rather than how to translate and disseminate such interventions into different settings for diverse populations, or external validity. Using the Reach, Efficacy/Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework, we conducted a systematic review to report how existing research reports external validity.
Assuntos
Promoção da Saúde , Obesidade Infantil , Criança , Humanos , Promoção da Saúde/métodos , Obesidade Infantil/prevenção & controle , Atenção Primária à SaúdeRESUMO
The annual meeting for the Intermountain Branch was held in April 2024 on the campus of Brigham Young University. There were 127 branch members from Utah, Idaho, and Nevada who attended the meeting and were composed of undergraduate students, graduate or medical students, and faculty. This report highlights the diversity of, and the emerging trends in, the research conducted by American Society for Microbiology members in the Intermountain Branch.
Assuntos
Microbiologia , Microbiologia/educaçãoRESUMO
In vivo studies have shown that selenium is supplied to testis and brain by apoER2-mediated endocytosis of Sepp1. Although cultured cell lines have been shown to utilize selenium from Sepp1 added to the medium, the mechanism of uptake and utilization has not been characterized. Rat L8 myoblast cells were studied. They took up mouse Sepp1 from the medium and used its selenium to increase their glutathione peroxidase (Gpx) activity. L8 cells did not utilize selenium from Gpx3, the other plasma selenoprotein. Neither did they utilize it from Sepp1(Δ240-361), the isoform of Sepp1 that lacks the selenium-rich C-terminal domain. To identify Sepp1 receptors, a solubilized membrane fraction was passed over a Sepp1 column. The receptors apoER2 and Lrp1 were identified in the eluate by mass spectrometry. siRNA experiments showed that knockdown of apoER2, but not of Lrp1, inhibited (75)Se uptake from (75)Se-labeled Sepp1. The addition of protamine to the medium or treatment of the cells with chlorate also inhibited (75)Se uptake. Blockage of lysosome acidification did not inhibit uptake of Sepp1 but did prevent its digestion and thereby utilization of its selenium. These results indicate that L8 cells take up Sepp1 by an apoER2-mediated mechanism requiring binding to heparin sulfate proteoglycans. The presence of at least part of the selenium-rich C-terminal domain of Sepp1 is required for uptake. RT-PCR showed that mouse tissues express apoER2 in varying amounts. It is postulated that apoER2-mediated uptake of long isoform Sepp1 is responsible for selenium distribution to tissues throughout the body.
Assuntos
Endocitose/fisiologia , Proteínas Relacionadas a Receptor de LDL/metabolismo , Lisossomos/metabolismo , Mioblastos/metabolismo , Selenoproteínas/metabolismo , Animais , Linhagem Celular , Cloratos/farmacologia , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Proteínas Relacionadas a Receptor de LDL/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Lisossomos/genética , Camundongos , Camundongos Knockout , Mioblastos/citologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ratos , Receptores de LDL/genética , Receptores de LDL/metabolismo , Selenoproteínas/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
BACKGROUND: Sepp1 transports selenium, but its complete role in selenium homeostasis is not known. RESULTS: Deletion of Sepp1 in hepatocytes increases liver selenium at the expense of other tissues and decreases whole-body selenium by increasing excretion. CONCLUSION: Sepp1 production by hepatocytes retains selenium in the organism and distributes it from the liver to peripheral tissues. SIGNIFICANCE: Sepp1 is central to selenium homeostasis. Sepp1 is a widely expressed extracellular protein that in humans and mice contains 10 selenocysteine residues in its primary structure. Extra-hepatic tissues take up plasma Sepp1 for its selenium via apolipoprotein E receptor-2 (apoER2)-mediated endocytosis. The role of Sepp1 in the transport of selenium from liver, a rich source of the element, to peripheral tissues was studied using mice with selective deletion of Sepp1 in hepatocytes (Sepp1(c/c)/alb-cre(+/-) mice). Deletion of Sepp1 in hepatocytes lowered plasma Sepp1 concentration to 10% of that in Sepp1(c/c) mice (controls) and increased urinary selenium excretion, decreasing whole-body and tissue selenium concentrations. Under selenium-deficient conditions, Sepp1(c/c)/alb-cre(+/-) mice accumulated selenium in the liver at the expense of extra-hepatic tissues, severely worsening clinical manifestations of dietary selenium deficiency. These findings are consistent with there being competition for metabolically available hepatocyte selenium between the synthesis of selenoproteins and the synthesis of selenium excretory metabolites. In addition, selenium deficiency down-regulated the mRNA of the most abundant hepatic selenoprotein, glutathione peroxidase-1 (Gpx1), to 15% of the selenium-replete value, while reducing Sepp1 mRNA, the most abundant hepatic selenoprotein mRNA, only to 61%. This strongly suggests that Sepp1 synthesis is favored in the liver over Gpx1 synthesis when selenium supply is limited, directing hepatocyte selenium to peripheral tissues in selenium deficiency. We conclude that production of Sepp1 by hepatocytes is central to selenium homeostasis in the organism because it promotes retention of selenium in the body and effects selenium distribution from the liver to extra-hepatic tissues, especially under selenium-deficient conditions.
Assuntos
Hepatócitos/metabolismo , Selênio/metabolismo , Selenoproteína P/metabolismo , Animais , Transporte Biológico , Feminino , Homeostase , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Selenoproteína P/genéticaRESUMO
Previous studies suggest some effects of selenium on risk of several chronic diseases, which may be mediated through a small number of selenoenzymes with antioxidant properties. In this cross-sectional analysis of 195 participants from the Seattle Barrett's Esophagus Study who were free of esophageal cancer at the time of blood draw, we examined whether the number of the minor alleles in 26 tagging single nucleotide polymorphisms (SNP) of five selenoenzyme genes [i.e., glutathione peroxidase 1-4 (GPX1-4) and selenoprotein P (SEPP1)] was associated with activity of GPX1 in white blood cells and GPX3 in plasma, and concentrations of SEPP1 and markers of oxidative stress [malondialdehyde (MDA) and protein carbonyl content] in plasma. At the gene level, associations were observed between overall variation in GPX1 and GPX1 activity (P = 0.02) as well as between overall variation in GPX2 and SEPP1 concentrations (P = 0.03). By individual SNP, two variants in GPX1 (rs8179164 and rs1987628) showed a suggestive association with GPX1 activity (P = 0.10 and 0.08, respectively) and two GPX2 variants (rs4902346 and rs2071566) were associated with SEPP1 concentration (P = 0.004 and 0.002, respectively). Furthermore, two SNP in the SEPP1 gene (rs230813 and rs230819) were associated with MDA concentrations (P = 0.03 and 0.02, respectively). Overall, our study supports the hypothesis that common genetic variants in selenoenzymes affect their activity.
Assuntos
Glutationa Peroxidase/sangue , Glutationa Peroxidase/genética , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Polimorfismo de Nucleotídeo Único , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Carbonilação Proteica/genética , Fatores de Risco , Selênio/metabolismo , Selenoproteína P/sangue , Selenoproteína P/genética , Glutationa Peroxidase GPX1RESUMO
To assess potential benefits and liabilities from a proposed introduction of Asian Suminoe oysters, susceptibilities of exotic Crassostrea ariakensis and native C. virginica oysters were compared during exposures to pathogens endemic in temperate, mesohaline waters of Chesapeake Bay and sub-tropical, polyhaline Atlantic waters of southern Florida, USA. Cohorts of diploid, sibling oysters of both species were periodically tested for diseases while reared in mesocosms receiving ambient waters from the Choptank River, Maryland (>3 yr) or the Indian River Lagoon, Florida (10 to 11 mo). Haplosporidium sp. infections (e.g. MSX disease) were not detected in oysters from either site. Perkinsus sp. infections (dermo disease) occurred among members of both oyster species at both sites, but infections were generally of low or moderate intensities. A Bonamia sp. was detected by PCR of DNAs from tissues of both oyster species following exposure to Florida waters, with maximum PCR prevalences of 44 and 15% among C. ariakensis and C. virginica oysters respectively during June 2007. Among C. ariakensis oysters sampled during April to July 2007, a Bonamia sp. was detected in 31% of oysters by PCR (range 11 to 35%) and confirmed histologically in 10% (range 0 to 15%). Among simultaneously sampled C. virginica oysters, a Bonamia sp. was detected in 7% by PCR (range 0 to 15%), but histological lesions were absent. Although this is the first report of a Bonamia sp. from Florida waters, sequences of small subunit (SSU) rDNA and in situ hybridization (ISH) assays both identified the Florida pathogen as Bonamia exitiosa, which also infects oysters in the proximate waters of North Carolina, USA.
Assuntos
Crassostrea/parasitologia , Rios , Animais , Aquicultura , Crassostrea/classificação , Ecossistema , Florida , Haplosporídios/isolamento & purificação , Haplosporídios/fisiologia , Interações Hospedeiro-Parasita , Maryland , Especificidade da Espécie , Fatores de TempoRESUMO
Glutathione peroxidase-3 (Gpx3), the extracellular glutathione peroxidase synthesized largely in the kidney, binds to basement membranes of renal cortical epithelial cells. The present study assessed extrarenal expression of Gpx3 using RT-PCR and presence of Gpx3 protein using immunocytochemistry. Gpx3 expression was higher in kidney and epididymis than in other tissues. Gpx3 bound to basement membranes of epithelial cells in the gastrointestinal tract, the efferent ducts connecting the seminiferous tubules with the epididymis, the bronchi, and type II pneumocytes. It was not detected on the basement membrane of type I pneumocytes. Gpx3 was also present in the lumen of the epididymis. Transplantation of Gpx3(+/+) kidneys into Gpx3(-/-) mice led to Gpx3 binding to the same basement membranes to which it bound in Gpx3(+/+) mice but not to its presence in the epididymal lumen. These results show that Gpx3 from the blood binds to basement membranes of specific epithelial cells and indicate that the cells modify their basement membranes to cause the binding. They further indicate that at least two Gpx3 compartments exist in the organism. In one compartment, kidney supplies Gpx3 through the blood to specific basement membranes in a number of tissues. In the other compartment, the epididymis provides Gpx3 to its own lumen. Tissues other than kidney and epididymis express Gpx3 at lower levels and may supply Gpx3 to other compartments.
Assuntos
Membrana Basal/enzimologia , Trato Gastrointestinal/enzimologia , Glutationa Peroxidase/metabolismo , Rim/enzimologia , Células Epiteliais Alveolares/enzimologia , Animais , Brônquios/enzimologia , Epididimo/enzimologia , Epididimo/metabolismo , Células Epiteliais/enzimologia , Glutationa Peroxidase/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Túbulos Seminíferos/enzimologiaRESUMO
Introduction: Telehealth utilization has been steadily increasing for the past two decades and has been recognized for its ability to access rural and underserved populations. The advent of COVID-19 in March 2020 limited the feasibility of in-person healthcare visits which in turn increased telehealth demand and use. However, the long-term impacts of COVID-19 on the telehealth sector of the healthcare industry, and particularly on pediatric healthcare volume demand and subsequent expansion, are yet to be determined. Objective and Methods: To understand the impact of COVID-19 on telehealth utilization, volume demand, and expansion in one large pediatric healthcare system serving greater Dallas-Fort Worth, Texas, data on telehealth clinic visits by month, pre-COVID and post/current-COVID were compared. A quasi-experimental pretest-posttest design analysis compared telehealth visit counts from 54 ambulatory pediatric health specialties. Pre-post new patient counts were also analyzed via chi square. Results: Total telehealth visit counts significantly increased between March-October 2019 (2,033 visits) compared to March-October 2020 (54,276 visits). Mean monthly telehealth visits increased by 6,530 visits, or 2,569.75% over the same time period (p < 0.0001). In October 2020, total telehealth visits were still 1,194.78% above 2019 levels (345 visits in 2019 vs. 4467 visits in 2020). Discussion: Results here show a substantial volume increase in telehealth-delivered pediatric healthcare and resource utilization as a response to COVID-19. This provides a template for permanent adoption of pediatric telehealth delivery post pandemic. Further investigation is needed to determine impacts upon resource allocation, processes, and general models and standard of care to assist facilities and programs to better address the needs of the pediatric populations they serve in the post-COVID era.
RESUMO
BACKGROUND: The COVID-19 pandemic presents unique opportunities for preexisting school telemedicine programs to reach pediatric populations that might otherwise experience a lapse in health care services. METHODS: A retrospective analysis of one of the largest school-based telemedicine programs in the country, based in the Dallas-Fort Worth (DFW), Texas was conducted that included 7021 pediatric patients who engaged in telehealth visits from 2014 to 2019. RESULTS: Asthma or other respiratory disease was the primary diagnosis (28.4%), followed by injury or trauma (18.4%), digestive disorders (6.9%), and ear/eye/skin disease (6.9%). More participants were from the North (34.4%) and West (33.2%) ISD compared to the South (20.6%) and East (11.7%) schools. Likewise, the majority of COVID-19 cases were in the North (61.8%) and West (31.6%) DFW regions, leading to 989 (59.9%) and 551 (33.4%) deaths, respectively. CONCLUSIONS: School-based telehealth programs have the potential to reach large pediatric populations most in need of health care due to COVID-19-related lapses in services, and to address COVID-19-related health issues as schools reopen. In the future, utilization could be expanded to contact tracing, testing, and screening for COVID-19.