Transcriptomic profile investigations highlight a putative role for NUDT16 in sepsis.

Sepsis is an aberrant systemic inflammatory response mediated by the acute activation of the innate immune system. Neutrophils are important contributors to the innate immune response that controls the infection, but harbour the risk of collateral tissue damage such as thrombosis and organ dysfunction. A better understanding of the modulations of cellular processes in neutrophils and other blood cells during sepsis is needed and can be initiated via transcriptomic profile investigations. To that point, the growing repertoire of publicly accessible transcriptomic datasets serves as a valuable resource for discovering and/or assessing the robustness of biomarkers. We employed systematic literature mining, reductionist approach to gene expression profile and empirical in vitro work to highlight the role of a Nudix hydrolase family member, NUDT16, in sepsis. The relevance and implication of the expression of NUDT16 under septic conditions and the putative functional roles of this enzyme are discussed.

SysInflam HuDB, a Web Resource for Mining Human Blood Cells Transcriptomic Data Associated with Systemic Inflammatory Responses to Sepsis.

Sepsis develops after a dysregulated host inflammatory response to a systemic infection. Identification of sepsis biomarkers has been challenging because of the multifactorial causes of disease susceptibility and progression. Public transcriptomic data are a valuable resource for mechanistic discoveries and cross-studies concordance of heterogeneous diseases. Nonetheless, the approach requires structured methodologies and effective visualization tools for meaningful data interpretation. Currently, no such database exists for sepsis or systemic inflammatory diseases in human. Hence we curated SysInflam HuDB (http://sepsis.gxbsidra.org/dm3/geneBrowser/list), a unique collection of human blood transcriptomic datasets associated with systemic inflammatory responses to sepsis. The transcriptome collection and the associated clinical metadata are integrated onto a user-friendly and Web-based interface that allows the simultaneous exploration, visualization, and interpretation of multiple datasets stemming from different study designs. To date, the collection encompasses 62 datasets and 5719 individual profiles. Concordance of gene expression changes with the associated literature was assessed, and additional analyses are presented to showcase database utility. Combined with custom data visualization at the group and individual levels, SysInflam HuDB facilitates the identification of specific human blood gene signatures in response to infection (e.g., patients with sepsis versus healthy control subjects) and the delineation of major genetic drivers associated with inflammation onset and progression under various conditions.

Immunomodulatory Effects of Vitamin D Supplementation in a Deficient Population.

In addition to its canonical functions, vitamin D has been proposed to be an important mediator of the immune system. Despite ample sunshine, vitamin D deficiency is prevalent (>80%) in the Middle East, resulting in a high rate of supplementation. However, the underlying molecular mechanisms of the specific regimen prescribed and the potential factors affecting an individual's response to vitamin D supplementation are not well characterized. Our objective is to describe the changes in the blood transcriptome and explore the potential mechanisms associated with vitamin D3 supplementation in one hundred vitamin D-deficient women who were given a weekly oral dose (50,000 IU) of vitamin D3 for three months. A high-throughput targeted PCR, composed of 264 genes representing the important blood transcriptomic fingerprints of health and disease states, was performed on pre and post-supplementation blood samples to profile the molecular response to vitamin D3. We identified 54 differentially expressed genes that were strongly modulated by vitamin D3 supplementation. Network analyses showed significant changes in the immune-related pathways such as TLR4/CD14 and IFN receptors, and catabolic processes related to NF-kB, which were subsequently confirmed by gene ontology enrichment analyses. We proposed a model for vitamin D3 response based on the expression changes of molecules involved in the receptor-mediated intra-cellular signaling pathways and the ensuing predicted effects on cytokine production. Overall, vitamin D3 has a strong effect on the immune system, G-coupled protein receptor signaling, and the ubiquitin system. We highlighted the major molecular changes and biological processes induced by vitamin D3, which will help to further investigate the effectiveness of vitamin D3 supplementation among individuals in the Middle East as well as other regions.

A literature-based approach for curating gene signatures in multifaceted diseases.

BACKGROUND AND AIMS: The task of identifying a representative and yet manageable target gene list for assessing the pathogenesis of complicated and multifaceted diseases is challenging. Using Inflammatory Bowel Disease (IBD) as an example, we conceived a bioinformatic approach to identify novel genes associated with the various disease subtypes, in combination with known clinical control genes. METHODS: From the available literature, we used Acumenta Literature LabTM (LitLab), network analyses, and LitLab Gene Retriever to assemble a gene pool that has a high likelihood of representing immunity-related subtype-specific signatures of IBD. RESULTS: We generated six relevant gene lists and 21 intersections that contain genes with unique literature associations to Crohn's Disease (n = 60), Ulcerative Colitis (n = 17), and unclassified (n = 45) subtypes of IBD. From this gene pool, we then filtered and constructed, using network analysis, a final list of 142 genes that are the most representative of the disease and its subtypes. CONCLUSIONS: In this paper, we present the bioinformatic construction of a gene panel that putatively contains subtype signatures of IBD, a multifactorial disease. These gene signatures will be tested as biomarkers to classify patients with IBD, which has been a clinically challenging task. Such approach to diagnose and monitor complicated disease pathogenesis is a stepping-stone towards personalized care.

Maintaining tissue selenium species distribution as a potential defense mechanism against methylmercury toxicity in juvenile white sturgeon (Acipenser transmontanus).

Selenium (Se) has been shown to antagonize mercury (Hg) toxicity. We have previously demonstrated that orally intubated selenomethionine (SeMet) and methylmercury (MeHg) reduced tissue Se accumulation, as well as blood and kidney Hg concentrations in juvenile white sturgeon (Acipenser transmontanus). However, the form of Se accumulated is not known. In this study, three organoseleniums: selenocysteine (Sec), Se-methyl-selenocysteine (MSeCys), and SeMet and two inorganic Se species: selenate and selenite were determined and quantified in the blood at different post-intubation periods (12, 24, 48h) and in the muscle, liver, and kidneys at 48h in white sturgeon orally intubated with a single dose of control (carrier), SeMet (500µg Se/kg body weight; BW), MeHg (850µg Hg/kg BW), and both (Se+Hg; at 500µg Se/kg and 850µg Hg/kg BW). When only SeMet was intubated, the accumulative/unmodified pathway took precedent in the blood, white muscle, liver, and kidneys. In the presence of MeHg, however, active metabolic transformation and de novo synthesis of biologically active Se forms are seen in the liver and kidneys, as indicated by a gradual increase in blood Sec:SeMet ratios and Se metabolites. In the white muscle, mobilization of endogenous Se storage by MeHg is supported by the absence of tissue SeMet and detectable levels of blood SeMet. In contrast, co-intubation with SeMet increased muscle SeMet. The high levels of unknown Se metabolites and detectable levels of selenite in the kidney reflect its role as the major excretory organ for Se. Selenium metabolism is highly regulated in the kidneys, as Se speciation was not affected by MeHg or by its co-intubation with SeMet. In the Se+Hg group, the proportion of SeMet in the liver has decreased to nearly 1/8th of that of the SeMet only group, resulting in a more similar selenocompound distribution profile to that of the MeHg only group. This is likely due to the increased need for Se metabolites necessary for MeHg demethylation in the liver. Our study demonstrated that in the presence of MeHg, regulating tissue Se speciation, hence, Se bioavailability, is more an important strategy than maintaining total Se levels in major organs of juvenile white sturgeon.

The interactive effects of selenomethionine and methylmercury on their absorption, disposition, and elimination in juvenile white sturgeon.

Selenium (Se) and mercury (Hg) are prevalent pollutants of industrialized watersheds. However, when co-administered, Se has protective effects on organisms from Hg. The mechanism is not fully understood, but it is thought that Se reduces Hg availability, either by forming biologically inert complexes and/or associating with selenoproteins. Despite concerns with aquatic contaminations, relatively little information is available on the interaction in aquatic organisms. In the present study, the interactive effects of Se and Hg on their absorption, disposition, and elimination were examined in juvenile white sturgeon, a benthic fish species at high risk to exposures of both contaminants. Selenium and Hg were provided as L-selenomethionine (SeMet) and methylmercury (MeHg), respectively. Groups of 10 sturgeon were orally intubated with a single dose of either 0 (control), SeMet (500 µg Se/kg body weight; BW), MeHg (850 µg Hg/kg BW), or their combination (Se/Hg; 500 µg Se/kg and 850 µg Hg/kg BW). The blood was repeatedly sampled and urine collected from the fish, over a 48 h post intubation period. At 48 h, the fish were sacrificed for Se and Hg tissue concentration and distribution. The co-administration of SeMet and MeHg significantly (p<0.05) lowered blood concentrations of both Se and Hg and tissue Se concentrations. Similarly, assimilation of Se and Hg was also reduced significantly. The interaction has a more quantitative effect on Se metabolism because the reduction in the overall tissue Se is a consequence of reduced Se absorption at the gut and not from the metabolic effects after absorption. In contrast, given the pulse increase in blood Hg concentration, tissue redistribution, and increased urinary elimination, the interactive effect on tissue Hg concentration is likely to be post-absorption. Even in the absence of exogenous SeMet, Se and Hg co-accumulated in tissue at a Se:Hg molar ratio greater than 1. Thus, similar to mammals, maintaining at least a 1:1 molar ratio of Se and Hg is of great physiological importance in the white sturgeon. Interestingly, SeMet did not divert Hg from the brain. Allocation of Se from the kidneys may have occurred in order to maintain the high Se:Hg molar ratios in the brain of white sturgeon. In the current study, the combined use of kinetic analysis and that of the conventional approach of measuring tissue concentration changes provided a comprehensive understanding of the interactive effect of SeMet and MeHg on their respective metabolic processes in juvenile white sturgeon.

Absorption, distribution, and elimination of graded oral doses of methylmercury in juvenile white sturgeon.

Mercury (Hg) is toxic and is released into the environment from a wide variety of anthropogenic sources. Methylmercury (MeHg), a product of microbial methylation, enables rapid Hg bioaccumulation and biomagnification in the biota. Methylmercury is sequestered and made available to the rest of the biota through the benthic-detrital component leading to the high risk of exposure to benthic fish species, such as white sturgeon (Acipenser transmontanus). In the present study, a combined technique of stomach intubation, dorsal aorta cannulation, and urinary catheterization was utilized to characterize the absorption, distribution, and elimination of Hg in white sturgeon over a 48h exposure. Mercury, as methylmercury chloride, at either 0, 250, 500, or 1000 µg Hg/kg body weight, was orally intubated into white sturgeon, in groups of five. The blood was repeatedly sampled and urine collected from the fish over the 48h post intubation period, and at 48h, the fish were sacrificed for Hg tissue concentration and distribution determinations. The fractional rate of absorption (K), blood Hg concentration (µg/ml), tissue concentration (µg/g dry weight) and distribution (%), and urinary Hg elimination flux (µg/kg/h) are significantly different (p<0.05) among the MeHg doses. Complete blood uptake of Hg was observed in all MeHg treated fish by 12h. The maximal observed blood Hg concentration peaks are 0.56±0.02, 0.70±0.02, and 2.19±0.07 µg/ml (mean±SEM) for the 250, 500, and 1000 µgHg/kg body weight dose groups, respectively. Changes in blood Hg profiles can be described by a monomolecular function in all of the MeHg treated fish. The Hg concentration asymptote (A) and K are dose dependent. The relationship between A and the intubation dose, however, is nonlinear. Mercury levels in certain tissues are comparable to field data and longer-term study, indicating that the lower doses used in the current study are ecologically relevant for the species. Tissue Hg concentrations are in the following decreasing order: gastro-intestinal tract>kidney>spleen>gill>heart>liver>brain>white muscle and remaining whole body. At 48h, Hg was found to be preferentially distributed to metabolically active tissues. Digestibility is highest at the lowest MeHg dose. Measurable urinary Hg was observed in the fish treated with the highest MeHg dose, and a significant increase in the elimination flux was observed between 3 and 12h post intubation.

Selenocompounds in juvenile white sturgeon: evaluating blood, tissue, and urine selenium concentrations after a single oral dose.

Selenium (Se) is an essential micronutrient for all vertebrates, however, at environmental relevant levels, it is a potent toxin. In the San Francisco Bay-Delta, white sturgeon, an ancient Chondrostean fish of high ecological and economic value, is at risk to Se exposure. The present study is the first to examine the uptake, distribution, and excretion of various selenocompounds in white sturgeon. A combined technique of stomach intubation, dorsal aorta cannulation, and urinary catheterization was utilized, in this study, to characterize the short-term effects of Se in the forms of sodium-selenate (Selenate), sodium-selenite (Selenite), selenocystine (SeCys), l-selenomethionine (SeMet), Se-methylseleno-l-cysteine (MSeCys), and selenoyeast (SeYeast). An ecologically relevant dose of Se (∼500 µg/kg body weight) was intubated into groups of 5 juvenile white sturgeon. Blood and urine samples were repeatedly collected over the 48 h post intubation period and fish were sacrificed for Se tissue concentration and distribution at 48 h. The tissue concentration and distribution, blood concentrations, and urinary elimination of Se significantly differ (p ≤ 0.05) among forms. In general, organic selenocompounds maintain higher blood concentrations, with SeMeCys maintaining the highest area under the curve (66.3 ± 8.7 and 9.3 ± 1.0 µg h/ml) and maximum Se concentration in blood (2.3 ± 0.2 and 0.4 ± 0.2 µg/ml) in both the protein and non-protein bound fractions, respectively. Selenate, however, did not result in significant increase of Se concentration, compared with the control, in the protein-bound blood fraction. Regardless of source, Se is preferentially distributed into metabolically active tissues, with the SeMet treated fish achieving the highest concentration in most tissues. In contrast, Selenite has very similar blood concentrations and tissue distribution profile to SeCys and SeYeast. From blood and tissue Se concentrations, Selenate is not stored in blood, but taken up rapidly by the liver and white muscle. Urinary elimination of Se is form dependent and peaks between 3 and 12 h post intubation. A basic understanding of the overall Se absorption, distribution, and elimination is provided through monitoring tissue Se concentrations, however, conclusions regarding to the dynamics and the specific processes of Se metabolism can only be inferred, in the absence of kinetic information.

Selenocompounds in juvenile white sturgeon: estimating absorption, disposition, and elimination of selenium using Bayesian hierarchical modeling.

The biological function of selenium (Se) is determined by its form and concentration. Selenium is an essential micronutrient for all vertebrates, however, at environmental levels, it is a potent toxin. In the San Francisco Bay-Delta, Se pollution threatens top predatory fish, including white sturgeon. A multi-compartmental Bayesian hierarchical model was developed to estimate the fractional rates of absorption, disposition, and elimination of selenocompounds, in white sturgeon, from tissue measurements obtained in a previous study (Huang et al., 2012). This modeling methodology allows for a population based approach to estimate kinetic physiological parameters in white sturgeon. Briefly, thirty juvenile white sturgeon (five per treatment) were orally intubated with a control (no selenium) or a single dose of Se (500 µg Se/kg body weight) in the form of one inorganic (Selenite) or four organic selenocompounds: selenocystine (SeCys), l-selenomethionine (SeMet), Se-methylseleno-l-cysteine (MSeCys), or selenoyeast (SeYeast). Blood and urine Se were measured at intervals throughout the 48h post intubation period and eight tissues were sampled at 48 h. The model is composed of four state variables, conceptually the gut (Q1), blood (Q2), and tissue (Q3); and urine (Q0), all in units of µg Se. Six kinetics parameters were estimated: the fractional rates [1/h] of absorption, tissue disposition, tissue release, and urinary elimination (k12, k23, k32, and k20), the proportion of the absorbed dose eliminated through the urine (f20), and the distribution blood volume (V; percent body weight, BW). The parameter k12 was higher in sturgeon given the organic Se forms, in the descending order of MSeCys > SeMet > SeCys > Selenite > SeYeast. The parameters k23 and k32 followed similar patterns, and f20 was lowest in fish given MSeCys. Selenium form did not affect k20 or V. The parameter differences observed can be attributed to the different mechanisms of transmucosal transport, metabolic reduction, and storage of the Se forms, which, in general, appear to be similar to that in mammals. We have demonstrated that the Bayesian approach is a powerful tool for integrating quantitative information from a study with sparse blood and urinary measurements and tissue concentrations from a single time point, while providing a full characterization of parameter variability. The model permits the quantitative mechanistic interpretation and predictions of Se absorption, disposition, and elimination processes. Furthermore, the model represents a first step towards population based physiological toxicokinetic modeling of Se in white sturgeon.