RESUMO
BACKGROUND: Heat stress (HS) has a negative impact on the intestinal barrier and immune function of pigs. Selenium (Se) may improve intestinal health through affecting selenoproteins. Thus we investigate the protective effect of new organic Se (2-hydroxy-4-methylselenobutanoic acid, HMSeBA) on jejunal damage in growing pigs upon HS and integrate potential roles of corresponding selenoproteins. RESULTS: HS decreased the villus height and increased (P < 0.05) the protein abundance of HSP70, and downregulated (P < 0.05) protein levels of tight junction-related proteins (CLDN-1 and OCLD). HS-induced jejunal damage was associated with the upregulation of four inflammation-related genes and ten selenoprotein-encoding genes, downregulation (P < 0.05) of four selenoprotein-encoding genes and decreased (P < 0.05) the protein abundance of GPX4 and SELENOS. Compared with the HS group, HMSeBA supplementation not only elevated the villus height and the ratio of V/C (P < 0:05), but also reduced (P < 0.05) the protein abundance of HSP70 and MDA content, and increased (P < 0.05) the protein abundance of OCLD. HMSeBA supplementation downregulated the expression of seven inflammation-related genes, changed the expression of 12 selenoprotein-encoding genes in jejunum mucosa affected by HS, and increased the protein abundance of GPX4, TXNRD1 and SELENOS. CONCLUSION: Organic Se supplementation beyond nutritional requirement alleviates the negative effect of HS on the jejunum of growing pigs, and its protective effect is related to the response of corresponding selenoproteins. © 2021 Society of Chemical Industry.
Assuntos
Transtornos de Estresse por Calor/veterinária , Mucosa Intestinal/imunologia , Jejuno/imunologia , Substâncias Protetoras/administração & dosagem , Selênio/administração & dosagem , Doenças dos Suínos/prevenção & controle , Animais , Suplementos Nutricionais/análise , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/imunologia , Transtornos de Estresse por Calor/genética , Transtornos de Estresse por Calor/imunologia , Transtornos de Estresse por Calor/prevenção & controle , Resposta ao Choque Térmico/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Selenoproteínas/genética , Selenoproteínas/imunologia , Suínos , Doenças dos Suínos/genética , Doenças dos Suínos/imunologiaRESUMO
Selenium (Se) is an essential trace chemical element that is widely distributed worldwide. Se exerts its immunomodulatory and nutritional activities in the human body in the form of selenoproteins. Se has increasingly appeared as a potential trace element associated with many human diseases, including hepatocellular carcinoma (HCC). Recently, increasing evidence has suggested that Se and selenoproteins exert their immunomodulatory effects on HCC by regulating the molecules of oxidative stress, inflammation, immune response, cell proliferation and growth, angiogenesis, signaling pathways, apoptosis, and other processes in vitro cell studies and in vivo animal studies. Se concentrations are generally low in tissues of patients with HCC, such as blood, serum, scalp hair, and toenail. However, Se concentrations were higher in HCC patient tissues after Se supplementation than before supplementation. This review summarizes the significant relationship between Se and HCC, and details the role of Se as a novel immunomodulatory or immunotherapeutic approach against HCC.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Selênio/uso terapêutico , Selenoproteínas/imunologia , Animais , Carcinoma Hepatocelular/imunologia , Humanos , Fatores Imunológicos/farmacologia , Neoplasias Hepáticas/imunologia , Selênio/farmacologiaRESUMO
Background: Selenium (Se) levels decrease in the circulation during acute inflammatory states and sepsis, and are inversely associated with morbidity and mortality. A more specific understanding of where selenoproteins and Se processing are compromised during insult is needed. We investigated the acute signaling response in selenoenzymes and Se processing machinery in multiple organs after innate immune activation in response to systemic lipopolysaccharide (LPS). Methods: Wild type (WT) adult male C57/B6 mice were exposed to LPS (5 mg/kg, intraperitoneal). Blood, liver, lung, kidney and spleen were collected from control mice as well as 2, 4, 8, and 24 h after LPS. Plasma Se concentration was determined by ICP-MS. Liver, lung, kidney and spleen were evaluated for mRNA and protein content of selenoenzymes and proteins required to process Se. Results: After 8 h of endotoxemia, plasma levels of Se and the Se transporter protein, SELENOP were significantly decreased. Consistent with this timing, the transcription and protein content of several hepatic selenoenzymes, including SELENOP, glutathione peroxidase 1 and 4 were significantly decreased. Furthermore, hepatic transcription and protein content of factors required for the Se processing, including selenophosphate synthetase 2 (Sps2), phosphoseryl tRNA kinase (Pstk), selenocysteine synthase (SepsecS), and selenocysteine lyase (Scly) were significantly decreased. Significant LPS-induced downregulation of these key selenium processing enzymes was observed in isolated hepatocytes. In contrast to the acute and dynamic changes observed in the liver, selenoenzymes did not decrease in the lung, kidney or spleen. Conclusion: Hepatic selenoenzyme production and Se processing factors decreased after endotoxemia. This was temporally associated with decreased circulating Se. In contrast to these active changes in the regulation of Se processing in the liver, selenoenzymes did not decrease in the lung, kidney or spleen. These findings highlight the need to further study the impact of innate immune challenges on Se processing in the liver and the impact of targeted therapeutic Se replacement strategies during innate immune challenge.
Assuntos
Endotoxemia/imunologia , Fígado/imunologia , Selenoproteínas/imunologia , Animais , Endotoxemia/sangue , Glutationa Peroxidase , Hepatócitos , Rim/imunologia , Pulmão/imunologia , Masculino , Camundongos Endogâmicos C57BL , Selênio/sangue , Baço/imunologiaRESUMO
Selenium is a trace element essential to human health largely because of its incorporation into selenoproteins that have a wide range of protective functions. Selenium has an ongoing history of reducing the incidence and severity of various viral infections; for example, a German study found selenium status to be significantly higher in serum samples from surviving than non-surviving COVID-19 patients. Furthermore, a significant, positive, linear association was found between the cure rate of Chinese patients with COVID-19 and regional selenium status. Moreover, the cure rate continued to rise beyond the selenium intake required to optimise selenoproteins, suggesting that selenoproteins are probably not the whole story. Nonetheless, the significantly reduced expression of a number of selenoproteins, including those involved in controlling ER stress, along with increased expression of IL-6 in SARS-CoV-2 infected cells in culture suggests a potential link between reduced selenoprotein expression and COVID-19-associated inflammation. In this comprehensive review, we describe the history of selenium in viral infections and then go on to assess the potential benefits of adequate and even supra-nutritional selenium status. We discuss the indispensable function of the selenoproteins in coordinating a successful immune response and follow by reviewing cytokine excess, a key mediator of morbidity and mortality in COVID-19, and its relationship to selenium status. We comment on the fact that the synthetic redox-active selenium compound, ebselen, has been found experimentally to be a strong inhibitor of the main SARS-CoV-2 protease that enables viral maturation within the host. That finding suggests that redox-active selenium species formed at high selenium intake might hypothetically inhibit SARS-CoV-2 proteases. We consider the tactics that SARS-CoV-2 could employ to evade an adequate host response by interfering with the human selenoprotein system. Recognition of the myriad mechanisms by which selenium might potentially benefit COVID-19 patients provides a rationale for randomised, controlled trials of selenium supplementation in SARS-CoV-2 infection.
Assuntos
COVID-19/imunologia , Inflamação/imunologia , Selênio/imunologia , Selenoproteínas/imunologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Azóis/farmacologia , Azóis/uso terapêutico , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/imunologia , Citocinas/imunologia , Humanos , Inflamação/tratamento farmacológico , Isoindóis , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/uso terapêutico , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Inibidores de Protease Viral/farmacologia , Inibidores de Protease Viral/uso terapêutico , Tratamento Farmacológico da COVID-19RESUMO
Active immunization can protect individuals from infectious diseases in social insects. It is well established that trace elements are essential to the host immune system, but the related gene functions in insect social immunity are unknown. Here, we found that the levels of three free elements (Se, Ca and Cr) and selenoprotein T (SELT) expression were significantly decreased in the termite Reticulitermes chinensis Snyder during active immunization against the entomopathogenic fungus Metarhizium anisopliae (Metchnikoff) Sorokin. Thus, we further explored the role of the SELT gene in the active immunization of termites. After SELT was significantly silenced by RNAi, the nestmates of fungus-contaminated termites exhibited reduced antifungal activity and increased mortality, along with increased expression of the immune genes transglutaminase (TG) and transferrin (Tsf), indicating that the active immunization of termites was disrupted by SELT silencing. Moreover, the TG-knockdown nestmates of fungus-contaminated termites significantly decreased grooming behavior, antifungal activity and survival, despite the upregulation of SELT expression, also suggesting that the active immunization of termites was disrupted by the silencing of TG. These findings demonstrated that both SELT gene and TG gene play important roles in driving active immunization against the entomopathogenic fungus M. anisopliae in R. chinensis.
Assuntos
Imunidade Inata/genética , Proteínas de Insetos/genética , Isópteros/imunologia , Metarhizium/fisiologia , Selenoproteínas/genética , Transglutaminases/genética , Animais , Proteínas de Insetos/imunologia , Isópteros/enzimologia , Isópteros/genética , Isópteros/fisiologia , Selenoproteínas/imunologia , Transglutaminases/imunologiaRESUMO
Many of the 25 members of the selenoprotein family function as enzymes that utilize their selenocysteine (Sec) residues to catalyze redox-based reactions. However, some selenoproteins likely do not exert enzymatic activity by themselves and selenoprotein K (SELENOK) is one such selenoprotein family member that uses its Sec residue in an alternative manner. SELENOK is an endoplasmic reticulum (ER) transmembrane protein that has been shown to be important for ER stress and for calcium-dependent signaling. Molecular mechanisms for the latter have recently been elucidated using knockout mice and genetically manipulated cell lines. These studies have shown that SELENOK interacts with an enzyme in the ER membrane, DHHC6 (letters represent the amino acids aspartic acid, histidine, histidine, and cysteine in the catalytic domain), and the SELENOK/DHHC6 complex catalyzes the transfer of acyl groups such as palmitate to cysteine residues in target proteins, i.e., palmitoylation. One protein palmitoylated by SELENOK/DHHC6 is the calcium channel protein, the inositol 1,4,5-trisphosphate receptor (IP3R), which is acylated as a means for stabilizing the tetrameric calcium channel in the ER membrane. Factors that lower SELENOK levels or function impair IP3R-driven calcium flux. This role for SELENOK is important for the activation and proliferation of immune cells, and recently, a critical role for SELENOK in promoting calcium flux for the progression of melanoma has been demonstrated. This review provides a summary of these findings and their implications in terms of designing new therapeutic interventions that target SELENOK for treating cancers like melanoma.
Assuntos
Sinalização do Cálcio , Estresse do Retículo Endoplasmático , Proteínas de Neoplasias , Neoplasias , Selenoproteínas , Animais , Sinalização do Cálcio/genética , Sinalização do Cálcio/imunologia , Estresse do Retículo Endoplasmático/genética , Estresse do Retículo Endoplasmático/imunologia , Humanos , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Selenoproteínas/genética , Selenoproteínas/imunologia , Selenoproteínas/metabolismoRESUMO
Selenium (Se) functions as a cellular redox gatekeeper through its incorporation into proteins as the 21st amino acid, selenocysteine (Sec). Supplementation of macrophages with exogenous Se (as sodium selenite) downregulates inflammation and intracellular oxidative stress by effectively restoring redox homeostasis upon challenge with bacterial endotoxin lipopolysaccharide (LPS). Here, we examined the use of a standard Tandem Mass Tag (TMT)-labeling mass spectrometry-based proteomic workflow to quantitate and examine temporal regulation of selenoproteins in such inflamed cells. Se-deficient murine primary bone marrow-derived macrophages (BMDMs) exposed to LPS in the presence or absence of selenite treatment for various time periods (0-20 h) were used to analyze the selenoproteome expression using isobaric labeling and shotgun proteomic workflow. To overcome the challenge of identification of Sec peptides, we used the identification of non-Sec containing peptides downstream of Sec as a reliable evidence of ribosome readthrough indicating efficient decoding of Sec codon. Results indicated a temporal regulation of the selenoproteome with a general increase in their expression in inflamed cells in a Se-dependent manner. Selenow, Gpx1, Msrb1, and Selenom were highly upregulated upon stimulation with LPS when compared to other selenoproteins. Interestingly, Selenow appeared to be one amongst the highly regulated selenoproteins in macrophages that was previously thought to be mainly restricted to myocytes. Collectively, TMT-labeling method of non-Sec peptides offers a reliable method to quantitate and study temporal regulation of selenoproteins; however, further optimization to include Sec-peptides could make this strategy more robust and sensitive compared to other semi-quantitative or qualitative methods. Graphical Abstract.
Assuntos
Macrófagos/química , Selenoproteínas/análise , Sequência de Aminoácidos , Animais , Inflamação/imunologia , Lipopolissacarídeos/imunologia , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Proteômica/métodos , Selenoproteínas/imunologia , Espectrometria de Massas em Tandem/métodosRESUMO
Se is an important bioelement essential for a healthy immune system. Dietary Se influences both innate and adaptive immune responses. However, the effects of Se deficiency in chicken spleen are still unknown; thus, we designed an experiment to study the role of Se in chicken spleen. A total of 180 one-day-old sea blue white laying hens were randomly allocated into two groups (a control group and a Se-deficient group). The control group was fed a diet supplemented with sodium selenite with a final Se content of 0.15 mg/kg, and the Se-deficient group was fed a Se-deficient diet with a Se content of 0.033 mg/kg. Twenty selenoproteins and ten cytokines were investigated in detail. The expression levels of selenoproteins in spleen were determined via real-time qPCR at 15, 35, and 55 days, and cytokine levels were determined using ELISA at 15, 35, and 55 days. Protein-protein interaction predictions and principal component analysis were performed. We found that the selenoprotein mRNA levels were significantly lower (P < 0.05) in the Se-deficient group compared with the control group. The expression levels of IL-2, IL-1ß, IL-6, IFN-α, and IL-17 were significantly lower (P < 0.05), and the levels of IL-8, IL-10, IFN-γ, IFN-ß, and TNF-α were significantly higher (P < 0.05) in the Se-deficient group. These selenoproteins were positively correlated with component 1 and component 2 of the PCA, but the relationship between cytokines and principal components in spleens was very complex. The investigation showed that Se deficiency caused a reduction in selenoprotein gene expression and further affected certain cytokines levels. Our results provide some compensatory data about selenoproteins and cytokines in spleens of Se-deficient chickens and provide clues for further research on the relationship between selenoproteins and cytokines.
Assuntos
Citocinas/biossíntese , Citocinas/imunologia , Selênio/deficiência , Selênio/imunologia , Selenoproteínas/imunologia , Baço/imunologia , Animais , GalinhasRESUMO
Selenium (Se) is an essential trace element that functions in the form of the 21st amino acid, selenocysteine (Sec) in a defined set of proteins. Se deficiency is associated with pathological conditions in humans and animals, where incorporation of Sec into selenoproteins is reduced along with their expression and catalytic activity. Supplementation of Se-deficient population with Se has shown health benefits suggesting the importance of Se in physiology. An interesting paradigm to explain, in part, the health benefits of Se stems from the observations that selenoprotein-dependent modulation of inflammation and efficient resolution of inflammation relies on mechanisms involving a group of bioactive lipid mediators, prostanoids, which orchestrate a concerted action toward maintenance and restoration of homeostatic immune responses. Such an effect involves the interaction of various immune cells with these lipid mediators where cellular redox gatekeeper functions of selenoproteins further aid in not only dampening inflammation, but also initiating an effective and active resolution process. Here we have summarized the current literature on the multifaceted roles of Se/selenoproteins in the regulation of these bioactive lipid mediators and their immunomodulatory effects.
Assuntos
Prostaglandinas/imunologia , Prostaglandinas/metabolismo , Selênio/administração & dosagem , Selenoproteínas/imunologia , Selenoproteínas/metabolismo , Animais , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/metabolismo , Metabolismo dos Lipídeos , Ensaios Clínicos Controlados Aleatórios como Assunto , Selênio/imunologia , Selênio/metabolismo , Transdução de SinaisRESUMO
Selenium is an essential micronutrient that plays a crucial role in development and a wide variety of physiological processes including effect immune responses. The immune system relies on adequate dietary selenium intake and this nutrient exerts its biological effects mostly through its incorporation into selenoproteins. The selenoproteome contains 25 members in humans that exhibit a wide variety of functions. The development of high-throughput omic approaches and novel bioinformatics tools has led to new insights regarding the effects of selenium and selenoproteins in human immuno-biology. Equally important are the innovative experimental systems that have emerged to interrogate molecular mechanisms underlying those effects. This review presents a summary of the current understanding of the role of selenium and selenoproteins in regulating immune cell functions and how dysregulation of these processes may lead to inflammation or immune-related diseases.
Assuntos
Doenças do Sistema Imunitário/imunologia , Sistema Imunitário/imunologia , Inflamação/imunologia , Selênio/imunologia , Selenoproteínas/imunologia , Imunidade Adaptativa , Animais , Interações Hospedeiro-Patógeno , Humanos , Sistema Imunitário/metabolismo , Sistema Imunitário/fisiopatologia , Doenças do Sistema Imunitário/metabolismo , Doenças do Sistema Imunitário/fisiopatologia , Imunidade Inata , Inflamação/metabolismo , Inflamação/fisiopatologia , Leucócitos/imunologia , Leucócitos/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Selênio/administração & dosagem , Selênio/deficiência , Selênio/metabolismo , Selenoproteínas/metabolismo , Evasão TumoralRESUMO
Selenof (15-kDa selenoprotein; Sep15) is an endoplasmic reticulum (ER)-resident thioredoxin-like oxidoreductase that occurs in a complex with UDP-glucose:glycoprotein glucosyltransferase. We found that Selenof deficiency in mice leads to elevated levels of non-functional circulating plasma immunoglobulins and increased secretion of IgM during in vitro splenic B cell differentiation. However, Selenof knockout animals show neither enhanced bacterial killing capacity nor antigen-induced systemic IgM activity, suggesting that excess immunoglobulins are not functional. In addition, ER-to-Golgi transport of a target glycoprotein was delayed in Selenof knockout embryonic fibroblasts, and proteomic analyses revealed that Selenof deficiency is primarily associated with antigen presentation and ER-to-Golgi transport. Together, the data suggest that Selenof functions as a gatekeeper of immunoglobulins and, likely, other client proteins that exit the ER, thereby supporting redox quality control of these proteins.
Assuntos
Apresentação de Antígeno , Linfócitos B/imunologia , Retículo Endoplasmático/imunologia , Complexo de Golgi/imunologia , Imunoglobulina M/imunologia , Selenoproteínas/imunologia , Animais , Linfócitos B/citologia , Linhagem Celular , Retículo Endoplasmático/genética , Fibroblastos/citologia , Fibroblastos/imunologia , Complexo de Golgi/genética , Imunoglobulina M/genética , Camundongos , Camundongos Knockout , Selenoproteínas/genética , Baço/citologia , Baço/imunologiaRESUMO
Selenium is an essential micronutrient that is incorporated into at least 25 selenoproteins encoded by the human genome, many of which serve antioxidant functions. Because patients with inflammatory bowel disease (IBD) demonstrate nutritional deficiencies and are at increased risk for colon cancer due to heightened inflammation and oxidative stress, selenoprotein dysfunction may contribute to disease progression. Over the years, numerous studies have analyzed the effects of selenoprotein loss and shown that they are important mediators of intestinal inflammation and carcinogenesis. In particular, recent work has focused on the role of selenoprotein P (SEPP1), a major selenium transport protein which also has endogenous antioxidant function. These experiments determined SEPP1 loss altered immune and epithelial cellular function in a murine model of colitis-associated carcinoma. Here, we discuss the current knowledge of SEPP1 and selenoprotein function in the setting of IBD, colitis, and inflammatory tumorigenesis.
Assuntos
Carcinogênese/imunologia , Colite/imunologia , Neoplasias do Colo/imunologia , Doenças Inflamatórias Intestinais/imunologia , Estresse Oxidativo , Selênio/imunologia , Selenoproteínas/imunologia , Animais , Carcinogênese/metabolismo , Carcinogênese/patologia , Colite/complicações , Colite/metabolismo , Colite/patologia , Colo/imunologia , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/etiologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Glutationa Peroxidase/imunologia , Glutationa Peroxidase/metabolismo , Humanos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Selênio/metabolismo , Selenoproteína P/imunologia , Selenoproteína P/metabolismo , Selenoproteínas/metabolismoRESUMO
Selenium (Se) is generally known as an essential micronutrient and antioxidant for humans and animals. Aflatoxin B1 (AFB1) is a frequent contaminant of food and feed, causing immune toxicity and hepatotoxicity. Little has been done about the mechanisms of how Se protects against AFB1-induced immune toxicity. The aim of this present study is to investigate the protective effects of Se against AFB1 and the underlying mechanisms. The primary splenocytes isolated from healthy pigs were stimulated by anti-pig-CD3 monoclonal antibodies and treated by various concentrations of different Se forms and AFB1. The results showed that Se supplementation alleviated the immune toxicity of AFB1 in a dose-dependent manner, as demonstrated by increasing T-cell proliferation and interleukin-2 production. Addition of buthionine sulfoximine abrogated the protective effects of SeMet against AFB1. SeMet enhanced mRNA and protein expression of glutathione peroxidase 1 (GPx1), selenoprotein S (SelS), and thioredoxin reductase 1 without and with AFB1 treatments. Furthermore, knockdown of GPx1 and SelS by GPx1-specific siRNA and SelS-specific siRNA diminished the protective effects of SeMet against AFB1-induced immune toxicity. It is concluded that SeMet diminishes AFB1-induced immune toxicity through increasing antioxidant ability and improving GPx1 and SelS expression in splenocytes. This study suggests that organic selenium may become a promising supplementation to protect humans and animals against the decline in immunity caused by AFB1.
Assuntos
Aflatoxina B1/toxicidade , Glutationa Peroxidase/genética , Selênio/imunologia , Selenoproteínas/genética , Baço/citologia , Baço/imunologia , Ração Animal/análise , Animais , Células Cultivadas , Suplementos Nutricionais/análise , Glutationa Peroxidase/imunologia , Selenoproteínas/imunologia , Baço/efeitos dos fármacos , Baço/enzimologia , Suínos , Glutationa Peroxidase GPX1RESUMO
The plasticity of macrophages is evident in helminthic parasite infections, providing protection from inflammation. Previously we demonstrated that the micronutrient selenium induces a phenotypic switch in macrophage activation from a classically activated (pro-inflammatory; M1/CAM) toward an alternatively activated (anti-inflammatory; M2/AAM) phenotype, where cyclooxygenase (COX)-dependent cyclopentenone prostaglandin J2 (15d-PGJ2) plays a key role. Here, we hypothesize that dietary selenium modulates macrophage polarization toward an AAM phenotype to assist in the increasing clearance of adult Nippostrongylus brasiliensis, a gastrointestinal nematode parasite. Mice on a selenium-adequate (0.08 ppm) diet significantly augmented intestinal AAM presence while decreasing adult worms and fecal egg production when compared with infection of mice on selenium-deficient (<0.01 ppm) diet. Further increase in dietary selenium to supraphysiological levels (0.4 ppm) had very little or no impact on worm expulsion. Normal adult worm clearance and enhanced AAM marker expression were observed in the selenium-supplemented Trsp(fl/fl)Cre(WT) mice that express selenoproteins driven by tRNA(Sec) (Trsp), whereas N. brasiliensis-infected Trsp(fl/fl)Cre(LysM) selenium-supplemented mice showed a decreased clearance, with lowered intestinal expression of several AAM markers. Inhibition of the COX pathway with indomethacin resulted in delayed worm expulsion in selenium-adequate mice. This was rescued with 15d-PGJ2, which partially recapitulated the effect of selenium supplementation on fecal egg output in addition to increasing markers of AAMs in the small intestine. Antagonism of PPARγ blocked the effect of selenium. These results suggest that optimal expression of selenoproteins and selenium-dependent production of COX-derived endogenous prostanoids, such as Δ(12)-PGJ2 and 15d-PGJ2, may regulate AAM activation to enhance anti-helminthic parasite responses.
Assuntos
Regulação da Expressão Gênica/imunologia , Ativação de Macrófagos , Macrófagos/imunologia , Nippostrongylus/imunologia , Selenoproteínas/imunologia , Infecções por Strongylida/imunologia , Animais , Suplementos Nutricionais , Macrófagos/parasitologia , Macrófagos/patologia , Masculino , Camundongos , Prostaglandina D2/análogos & derivados , Prostaglandina D2/imunologia , Selênio/farmacologia , Infecções por Strongylida/tratamento farmacológicoRESUMO
Selenium (Se) deficiency induces hemolysis in chickens, but the molecular mechanism for this effect remains unclear. Se primarily elicits its function through the activity of selenoproteins, which contain the unique amino acid selenocysteine (Sec). In this study, we aimed to investigate the effect of Se deficiency on the expression of 24 selenoproteins and 10 cytokines. One hundred eighty chickens were randomly divided into 2 groups (90 chickens per group). During the entire experimental period, chickens were allowed ad libitum consumption of feed and water. The chickens were fed either a Se-deficient diet (0.008 mg Se/kg; produced in the Se-deficient area of Heilongjiang, China) or a Se-supplemented diet (as sodium selenite) at 0.2 mg/kg for 35 days. At the 35th day, the messenger RNA (mRNA) levels of 24 selenoproteins and 10 cytokines were examined in erythrocytes of 5 chickens per group, and the correlation was analyzed. The results showed that the expression of 24 selenoproteins and 7 cytokines (IL-2, IL-4, IL-8, IL-10, IL-12ß, TGF-ß4, and IFN-γ) decreased (P < 0.05), and the expression of 3 cytokines (IL-1γ, IL-6 and IL-7) was higher in the Se-deficient group. In both groups, glutathione peroxidase (GPX), thioredoxin 1 (Txnrd1), selenoprotein P1 (SELP), and selenoprotein synthetase (SPS2) were highly expressed compared to the other selenoproteins in chicken erythrocytes (P < 0.05). These data suggest that GPXs, Txnrd1, SELP, and SPS2 possibly play a more important role than the other selenoproteins. The increase of pro-inflammatory cytokines (IL-1γ, IL-6, and IL-7) suggested that the immune system of chickens was damaged by the Se deficiency. Correlation analysis suggested that although the expression of 24 selenoproteins and 7 cytokines decreased and that of 3 cytokines increased, there was a close correlation between their expression levels and a Se diet. These results suggested that Se deficiency influenced the expressions of 24 selenoproteins and 10 cytokines in chicken erythrocytes, revealing a relationship between Se and the chicken immune system. This study offers information regarding the mechanism of Se deficiency-induced hemolysis.
Assuntos
Citocinas/genética , Eritrócitos/metabolismo , Selênio/deficiência , Selenoproteínas/genética , Animais , Galinhas , Citocinas/imunologia , Citocinas/metabolismo , Eritrócitos/imunologia , Perfilação da Expressão Gênica , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Selênio/administração & dosagem , Selênio/metabolismo , Selenoproteínas/imunologia , Selenoproteínas/metabolismoRESUMO
Dietary intake of the micronutrient selenium is essential for normal immune functions. Selenium is cotranslationally incorporated as the 21st amino acid, selenocysteine, into selenoproteins that function to modulate pathways involved in inflammation. Epidemiological studies have suggested an inverse association between selenium levels and inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis that can potentially progress to colon cancer. However, the underlying mechanisms are not well understood. Here we summarize the current literature on the pathophysiology of IBD, which is multifactorial in origin with unknown etiology. We have focused on a few selenoproteins that mediate gastrointestinal inflammation and activate the host immune response, wherein macrophages play a pivotal role. Changes in cellular oxidative state coupled with altered expression of selenoproteins in macrophages drive the switch from a proinflammatory phenotype to an anti-inflammatory phenotype to efficiently resolve inflammation in the gut and restore epithelial barrier integrity. Such a phenotypic plasticity is accompanied by changes in cytokines, chemokines, and bioactive metabolites, including eicosanoids that not only mitigate inflammation but also partake in restoring gut homeostasis through diverse pathways involving differential regulation of transcription factors such as nuclear factor-κB and peroxisome proliferator-activated receptor-γ. The role of the intestinal microbiome in modulating inflammation and aiding in selenium-dependent resolution of gut injury is highlighted to provide novel insights into the beneficial effects of selenium in IBD.
Assuntos
Dieta , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/metabolismo , Selênio/metabolismo , Selenoproteínas/metabolismo , Animais , Neoplasias do Colo/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Intestinos/imunologia , Intestinos/microbiologia , Microbiota , Oxirredução , Fatores de Risco , Selênio/imunologia , Selenoproteínas/imunologia , Transdução de SinaisRESUMO
Inflammation is a hallmark of inflammatory bowel disease (IBD) that involves macrophages. Given the inverse link between selenium (Se) status and IBD-induced inflammation, our objective was to demonstrate that selenoproteins in macrophages were essential to suppress proinflammatory mediators, in part, by the modulation of arachidonic acid metabolism. Acute colitis was induced using 4% dextran sodium sulfate in wild-type mice maintained on Se-deficient (<0.01 ppm Se), Se-adequate (0.08 ppm; sodium selenite), and two supraphysiological levels in the form of Se-supplemented (0.4 ppm; sodium selenite) and high Se (1.0 ppm; sodium selenite) diets. Selenocysteinyl transfer RNA knockout mice (Trsp(fl/fl)LysM(Cre)) were used to examine the role of selenoproteins in macrophages on disease progression and severity using histopathological evaluation, expression of proinflammatory and anti-inflammatory genes, and modulation of PG metabolites in urine and plasma. Whereas Se-deficient and Se-adequate mice showed increased colitis and exhibited poor survival, Se supplementation at 0.4 and 1.0 ppm increased survival of mice and decreased colitis-associated inflammation with an upregulation of expression of proinflammatory and anti-inflammatory genes. Metabolomic profiling of urine suggested increased oxidation of PGE2 at supraphysiological levels of Se that also correlated well with Se-dependent upregulation of 15-hydroxy-PG dehydrogenase (15-PGDH) in macrophages. Pharmacological inhibition of 15-PGDH, lack of selenoprotein expression in macrophages, and depletion of infiltrating macrophages indicated that macrophage-specific selenoproteins and upregulation of 15-PGDH expression were key for Se-dependent anti-inflammatory and proresolving effects. Selenoproteins in macrophages protect mice from dextran sodium sulfate-colitis by enhancing 15-PGDH-dependent oxidation of PGE2 to alleviate inflammation, suggesting a therapeutic role for Se in IBD.
Assuntos
Colite/imunologia , Macrófagos/imunologia , Selenoproteínas/imunologia , Animais , Linhagem Celular , Colite/induzido quimicamente , Colite/patologia , Sulfato de Dextrana/toxicidade , Suplementos Nutricionais , Dinoprostona/genética , Dinoprostona/imunologia , Hidroxiprostaglandina Desidrogenases/genética , Hidroxiprostaglandina Desidrogenases/imunologia , Inflamação/genética , Inflamação/imunologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Aminoacil-RNA de Transferência/genética , Aminoacil-RNA de Transferência/imunologia , Selênio/farmacologia , Selenoproteínas/genéticaRESUMO
Inadequate dietary intake of the essential trace element selenium (Se) is thought to be a risk factor for several chronic diseases associated with oxidative stress and inflammation. Biological actions of Se occur through low-molecular weight metabolites and through selenoproteins. Several key selenoproteins including glutathione peroxidases; selenoproteins M, P, and S; and selenium-binding protein 1 have been detected in the intestine. Interestingly, Se and antioxidant selenoproteins are known to modulate differentiation and function of immune cells and contribute to avoid excessive immune responses. This review discusses the role of Se and intestinal selenoproteins in inflammatory bowel diseases, based on data from human, animal, and in vitro studies. In humans, Se deficiency is commonly observed in patients with Crohn's disease. In animal models of experimental colitis, the Se status was negatively correlated with the severity of the disease. While the cause-effect relationship of these observations remains to be clarified, the beneficial outcome of dietary Se supplementation and an optimization of selenoprotein biosynthesis in murine inflammatory bowel disease models have led to investigations of targets and actions of Se in the gastrointestinal tract. The Se status affects gene expression, signaling pathways, and cellular functions in the small and large intestine as well as the gut microbiome composition. This data, particularly from animal experiments, hold promise that adequate dietary Se supply may counteract chronic intestinal inflammation in humans.
Assuntos
Colite Ulcerativa/metabolismo , Doença de Crohn/metabolismo , Selênio/metabolismo , Selenoproteínas/metabolismo , Animais , Colite Ulcerativa/dietoterapia , Colite Ulcerativa/imunologia , Doença de Crohn/dietoterapia , Doença de Crohn/imunologia , Suplementos Nutricionais , Modelos Animais de Doenças , Humanos , Selênio/imunologia , Selenoproteínas/imunologiaRESUMO
Previously, we reported that feeding selenium (Se)-enriched forage improves antibody titers in mature beef cows, and whole-blood Se concentrations and growth rates in weaned beef calves. Our current objective was to test whether beef calves fed Se-enriched alfalfa hay during the transition period between weaning and movement to a feedlot also have improved immune responses and slaughter weights. Recently weaned beef calves (n = 60) were fed an alfalfa-hay-based diet for 7 weeks, which was harvested from fields fertilized with sodium selenate at 0, 22.5, 45.0, or 89.9 g Se/ha. All calves were immunized with J-5 Escherichia coli bacterin. Serum was collected for antibody titers 2 weeks after the third immunization. Whole-blood neutrophils collected at 6 or 7 weeks were evaluated for total antioxidant potential, bacterial killing activity, and expression of genes associated with selenoproteins and innate immunity. Calves fed the highest versus the lowest level of Se-enriched alfalfa hay had higher antibody titers (P = 0.02), thioredoxin reductase-2 mRNA levels (P = 0.07), and a greater neutrophil total antioxidant potential (P = 0.10), whereas mRNA levels of interleukin-8 receptor (P = 0.02), L-selectin (P = 0.07), and thioredoxin reductase-1 (P = 0.07) were lower. In the feedlot, calves previously fed the highest-Se forage had lower mortality (P = 0.04) and greater slaughter weights (P = 0.02). Our results suggest that, in areas with low-forage Se concentrations, feeding beef calves Se-enriched alfalfa hay during the weaning transition period improves vaccination responses and subsequent growth and survival in the feedlot.